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Current Alzheimer Research, 2017, 14, 1-12
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REVIEW ARTICLE
Seeing Early Signs of Alzheimer’s Disease Through the Lens of the Eye
a,b,c,d
Brian T. Reed
a,b,c,d
, Francine Behar-Cohen
a,b,c,d,*
and Slavica Krantic
a
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris,
France; bINSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France; cUniversité Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France; d Centre National de la Recherche Scientifique (ou CNRS) ERL 8228, Centre de Recherche des Cordeliers, Paris, France
ARTICLE HISTORY
Received: January 10, 2016
Revised: August 01, 2016
Accepted: August 10, 2016
DOI: 10.2174/1567205013666160819
131904
Abstract: Alzheimer's disease (AD) develops undetected for years due to the lack of early diagnostic
biomarkers. In advanced AD, visual deficits related to cortical neurodegeneration are well recognized,
but recent studies have identified that the retina could be affected prior to vulnerable brain areas such
as cortex and hippocampus. In this review, we focus on new evidence suggesting that synaptic dysfunction within the retina may be reminiscent of changes within the brain. The data on the earliest dysfunction of synaptic and neuronal networks in vulnerable brain areas (mostly cortex and hippocampus)
are next discussed to point out how they may inspire the analogous research in the retina during the asymptomatic stage of AD. We finally present evidence indicating why putative retinal synaptic dysfunction holds the potential to become the earliest sign of AD, allowing for a non-invasive and easy
detection using modern imaging and functional techniques. Translation of these findings to clinical diagnosis could lead to earlier therapeutic interventions and, consequently, better chances to delay or halt
AD progression.
Keywords: Alzheimer’s Disease, neurodegeneration, amyloid plaques, tau protein, glial activation.
1. INTRODUCTION
Alzheimer’s disease (AD), a neurodegenerative disease
with poorly understood pathogenesis, is the leading cause of
dementia in elderly. The number of patients with AD and
related dementias is estimated to 44 million people worldwide (http://www.alz.co.uk/research/world-report-2014).
The currently available AD treatments are all palliative.
They include rivastigmine, galantamine and donepezil which
all target cholinergic neurotransmission. Memantine, an antagonist of N-methyl D-aspartate (NMDA)-type of glutamate
receptors, is the last AD drug approved for clinical use.
However, the benefit provided by these drugs used to treat
mild to moderate stages of AD is only limited. Indeed, the
current treatments provide partial relief of cognitive symptoms only in a sub-population of patients, and their efficacy
has been recently questioned in some countries, such as
France (http://www.has-sante.fr/portail/upload/docs/application/pdf/2011-11/rapport_evaluation_mdc_alzheimer).
The lack of curative treatments has recently motivated a
“shift in focus” towards earlier diagnosis of AD which
should allow for the earlier application of the existing
treatments. The rationale is that the earlier application of the
available treatments may translate to better efficacy. In addition, due to the long latency between the beginning of AD
*Address correspondence to this author at the Centre de Recherche des
Cordeliers, UMRS 1138, équipe 17, 15, rue de l’école de médecine, 75 006
Paris, France; Tel: (33) 144 - 278 - 187; Fax: (33) 144 - 279- 036;
E-mail: [email protected]
1567-2050/17 $58.00+.00
pathogenesis and the manifestation of the clinical symptoms,
earlier diagnosis may allow for application of non-medicinal
intervention strategies (cognitive enhancement, healthy diet,
exercise, etc.) to prevent the onset of full-blown AD pathology and its progression towards irreversible neurodegeneration. Such a “shift in focus” relies obviously on the discovery of early diagnostic biomarkers.
In this review, we will discuss the evidence pointing to
the retina as a potential source of the earliest diagnostic tissue for AD. This discussion is preceded by a short presentation of the physiological function of the retina and of the
current methods that can be used for non-invasive retinal
exploration of neurodegenerative changes. Early diagnosis of
AD utilizing changes in the retina remains challenging because of the similarities between the pathogenesis of AD,
glaucoma and age-related macular degeneration (AMD).
These similarities are confounding in terms of diagnosis because they exhibit a high incidence of comorbidity with AD
(e.g. glaucoma and AD). However, these aspects will not be
discussed here. Instead, recently published reviews on these
topics are recommended [1, 2]. Although all parts of the visual system and, more specifically, the visual cortex, have
been reported to be affected in the advanced stages of AD
[2], in this review, we focus exclusively on the retina. Finally, we provide arguments in favour of monitoring retinal
neuronal activity for the purpose of identification of the earliest AD biomarkers using non-invasive diagnostic exploration.
© 2017 Bentham Science Publishers
2 Current Alzheimer Research, 2017, Vol. 14, No. 1
1.1. Background on AD
AD comprises a number of progressive and age-related
cognitive and behavioral impairments. The main neuropathological hallmark of AD is the accumulation of amyloidbeta (Aβ) peptide produced by successive proteolytic cleavage from its precursor APP (amyloid-beta precursor protein)
along the amyloidogenic pathway [3]. Aβ accumulates extracellularly as amyloid plaques (or senile plaques). Intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein are also a prominent pathological feature of
AD [4].
The cause of sporadic AD is still unknown and among
different theories proposed for AD pathogenesis, the amyloid
cascade hypothesis is currently the most generally accepted.
This hypothesis postulates that the overproduction of Aβ
from its precursor APP triggers a series of events, including
synaptic dysfunction, glial activation and hyperphosphorylation of tau, which are associated with widespread neuronal
death [4]. The amyloid hypothesis is supported by strong
genetic evidence coming from the pathogenesis of rare (25%) familial forms of AD. Patients suffering from the familial forms of AD bear mutations in the APP gene, which yield
overproduction of Aβ and is therefore more prone to aggregation. The additional genetic mutations leading to AD were
identified in the genes encoding presenilin 1 and 2, PSEN1
and PSEN2, respectively. However, although the familial
and the much more frequently occuring (95-98%) sporadic
forms of AD share the same hallmark histopathological lesions (notably extracellular plaques and intracellular tangles), the etiology of the sporadic form remains unknown.
Remarkably, experimental mutations in APP or presenilins
recapitulate many of the pathological features of AD and
provide solid support for the amyloid cascade hypothesis.
The majority of transgenic mouse models of AD were generated based on the over-expression of mutated human APP,
PS1/2 genes, as well as of their combined mutations into the
mouse genome. These mice are commonly used to develop
and test new treatments. It has however been recently recognized that the transgenic AD mouse models which are based
on the amyloid cascade hypothesis, mimic faithfully only the
initial stages of AD pathogenesis [5].
1.2. Current Diagnostic Tools for AD
Currently, AD diagnosis is mainly based on the clinical
symptoms such as loss of cognitive functions that affect the
individuals’ autonomy in executive daily tasks. Cognitive
impairments include short-term, which precedes long-term,
memory loss as the disease progresses. Cognitive symptoms
are often combined with neurological (seizures, parkinsonism-like alterations), behavioral (agitation, sleep disturbances, aggression) and neuropsychiatric (depression, paranoia, hallucinations) symptoms. Some of these symptoms are
clinically discernable at the time of diagnosis (anxiety, depression) whilst others (paranoia, hallucinations) appear later
in the course of the natural history of AD. However, the
clinical panel of symptoms is considerably heterogeneous
with important inter-individual differences. Such a heterogeneous panel of symptoms complicates diagnosis.
The systematic follow-up of individuals at risk of developing the familial form of AD due to autosomal dominant
Reed et al.
mutations allowed for the estimation of the age of AD onset
based on the age at which the parents began experiencing
symptoms. An increased level of Aβ in the cerebrospinal
fluid has been detected as early as 25 years before the expected age of AD onset [6]. Relevantly, monitoring Aβ (and
hyperphosphorylated tau) levels in the cerebrospinal fluid
had initially raised much hope that they could serve as early
diagnostic biomarkers for AD [7-9]. However, it turned out
that either Aβ or hyperphosphorylated tau alone do not
provide sufficient diagnostic accuracy likely because AD is a
multifactorial, complex disease. According to the current
view, combining Aβ and hyperphosphorylated biomarkers
with structural and functional brain changes, as well as with
follow-up of memory impairments, may allow more reliable
diagnosis (reviewed in [10]). Furthermore, Aβ plaque imaging by Positron Emission Tomography (PET) with radiolabeled (C-11) or F18 counterpart of Pittsburgh compound-B
(PiB) was also considered to be a helpful diagnostic tool [7,
11, 12]. Unfortunately, PET screening turned out to detect a
high PiB retention in one third of cognitively normal elderly
subjects [7, 11, 13]. Limited availability of PET facilities and
the high cost of the procedure, combined with a high percentage of the “false-positives” make PiB screening unlikely
to become a general tool for early AD diagnosis.
1.3 Alterations of Neuronal Functions in AD
Despite the “shift in focus” towards identifying the putative early biomarkers for AD, it has been recognized for at
least the last 20 years that synaptic loss represents the best
functional correlate for cognitive impairment [14]. More
recently, it became clear that the alteration in synaptic activity precedes neuronal loss, and subsequent repercussions at
the neuronal circuit and network levels may also be considered as attractive candidates for an early diagnostic tool.
1.3.1. Synaptic Dysfunctions
The vast majority of published data on the early synaptic
dysfunction investigated brain regions such as hippocampus
and cortex that are known to be the most vulnerable to AD.
The Aβ-sensitive deviations from normal synaptic function
are detectable at both molecular and cellular levels. Gene
expression studies have found abnormal patterns of neuronal
activity before the onset of overt AD symptoms. For instance, Arc is often over- or under-expressed in the hippocampus of pre-plaque AD model mice that express high
soluble Aβ levels [15, 16]. This is an important finding since
the fluctuations in expression of this synaptic activitydependent gene indicates network instability.
At the cellular level, Aβ-mediated alterations of synaptic
transmission involve, among other mechanisms, direct impact on glutamatergic signaling pathways. Ionotropic glutamate receptors (iGluR), α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) and NMDA receptors are
particularly sensitive to Aβ. In the hippocampus of AD mice
(hAPPJ20), the expressions of AMPA- and NMDA receptors
at the post-synaptic membrane are both reduced [17]. The
mechanism of Aβ-mediated decrease in surface AMPA receptor expression involves increased intracellular calcium
levels and phosphorylation of glutamate receptor subunit 2
(GluR2) [18]. In the case of NMDA receptors, decreased
expression at the post-synaptic membrane likely stems from
Seeing Early Signs of Alzheimer’s Disease
Aβ-promotion of receptor trafficking from the synaptic- towards the extra-synaptic location [19]. The reported decrease
in NMDA and AMPA receptor expression has been further
associated with the loss of dendritic spines in the postsynaptic compartment of the excitatory synapses in both AD
mice [20-23] and human post-mortem studies [24, 25].
In addition to their direct effect on iGluR, soluble Aβ oligomers have been reported to impact glutamatergic neurotransmission indirectly by modulating the activity of other
types of receptors. For example, Aβ oligomers interact with
nicotinic acetylcholine receptors (α7-nAChRs) yielding a
decreased calcium response [26], which may be related to
subsequent alterations in neuronal excitability [17]. Consistently, α7-nAChRs are required for Aβ-mediated increased
endocytosis of post-synaptic NMDA receptors subsequent to
NR2B subunit dephosphorylation [19]. This results in a rapid
and a persistent decrease of NMDA-evoked currents in primary cultures of cortical neurons [19]. All data discussed
above that lead to alterations in glutamatergic neurotransmission.
However, calcium imaging studies have found that hyper- and hyporeactive neurons coexist in the cortex of
APP/PS1 double transgenic mice during the early stages of
pathogenesis [27]. More recently, the same group has reported that in the hippocampus, both silent and hyperactive
neurons occur in the vicinity of Aβ-plaques [28]. Remarkably, the hyperactive neurons have also been identified in the
absence of Aβ-plaques in the hippocampus of young, asymptomatic APP/PS1 mice using bi-photon calcium imaging
[28]. Regarding the neuronal hyperactivity, Minkeviciene
and colleagues have shown that glutamatergic pyramidal
cells in the cortex of APP/PS1 mice have more depolarized
resting membrane potentials, lower action potential initiation
threshold, and generate more action potentials to a given
stimulus at a higher frequency [29]. All of these alterations
have been detected well before the onset of the overt AD
pathology, and in particular before a significant accumulation of Aβ-plaques [29]. Similar findings were obtained in
another strain of AD mice (TgCRND8). In the latter study,
the resting calcium levels in CA1 pyramidal neurons were
found to be higher in pre-plaque (2 months-old) TgCRND8
mice than in controls [30]. Interestingly, this study has also
shown that in young, asymptomatic TgCRND8 mice, there
was a narrowing of the action potential waveform, which is
likely related to the observed increase in Kv3-type fast delayed rectifier potassium current. Most importantly, these
subtle alterations occur weeks and perhaps months before
any other synaptic alteration (paired-pulse ratio,
AMPA/NMDA receptor ratio, miniature excitatory postsynaptic potentials (ESPS), or expression of other potassium
and sodium ionic channels) could be detected [30].
1.3.2. Neuronal Circuit and Network Impairments
Neuronal organization into circuits, and at the higher
level, neuronal networks, is superimposed onto neuronal
communication via synaptic neurotransmission. This communication has to be coordinated in order to support cognitive function, notably learning and memory. An adaptive
value of such organization may be linked to the capacity of
the network, at least during the very first stages of AD, to
compensate for the aberrant excitatory synaptic activity (dis-
Current Alzheimer Research, 2017, Vol. 14, No. 1
3
cussed above) by remodeling of inhibitory synaptic circuits
[17].
In addition to its effects on synaptic function, Aβ can induce changes at the higher levels of brain organization complexity. As for neuronal circuits, long term potentiation
(LTP) and long term depression (LTD) have been reported as
Aβ-sensitive targets [31, 32], in line with the fact that increased and decreased surface expression of AMPA receptors may underlie LTP and LTD, respectively. LTP and LTD
are indeed recognized as a cellular basis of learning and
memory and deficits are present in early stages of AD [33,
34].
Pioneering work from Palop and colleagues was the first
to define the link between Aβ and hippocampal network dysregulation [17]. In particular, excessive network synchronization has been reported and linked to a specific type of inhibitory gamma-amino butyric-acid (GABA) neuron within
the hippocampus [35]. More specifically, Verret and colleagues have shown that restoring normal expression of a
specific voltage-gated sodium channel (Nav1.1) reduced
abnormal network synchronization and memory deficits in
hAPPJ20 mice [35]. In addition, the oscillatory activity of
neuronal networks is negatively affected by the hyperexcitability and impaired plasticity of synapses. Most importantly,
the hippocampal hyperactivation is correlated with cortical
thinning (a sensitive and specific marker of AD neurodegeneration) within MCI patients [36].
Increasing evidence suggests that cortical oscillatory activity in the theta [37-39] and gamma [40, 41] ranges are
altered in AD patients. While the extent of the changes in
hippocampal network activity in asymptomatic AD is still
unclear, changes in theta oscillations are viewed as a possible predictor of AD [42]. Furthermore, impairments in thetagamma cross-frequency coupling in hippocampus have been
reported in a pre-clinical mouse model of AD [43].
Therefore, at least in the hippocampus (Table 1), subtle
disturbances in the communication between groups of neurons and the synchronization of network activities may occur
much earlier than any other AD-related pathological lesion,
including Aβ accumulation [44]. These recent data suggest
that electrophysiological-based approaches may become a
sensitive alternative for detection of the early AD-related
dysfunction of neuronal activity and networking.
2. THE RETINA
The vertebrate retina is the layer of light-detecting tissue
lining the back of the eye. It contains neurons, glial cells, and
vascular tissue, and has a high level of metabolic activity. In
addition, the retina has an outermost layer, the retinal pigment epithelium. The retinal pigment epithelium provides
regulatory and nutrient factors to the neurons and plays an
important role in the homeostasis of the adjacent photoreceptors in the outer nuclear layer.
Glial cells of the retina comprise three major types:
Müller cells, astrocytes, and microglia [45, 46]. Müller cells
are the most common type of retinal glial cells. They span
the retina radially and maintain the homeostasis of the extracellular environment. As pigment epithelium cells, Müller
cells provide regulatory and nutrient support for the neigh-
4 Current Alzheimer Research, 2017, Vol. 14, No. 1
Table 1.
Reed et al.
Hippocampal dysfunctions in the brain of mouse AD models.
Target
Alteration
Type of change
References
Arc
Expression
+/-
[15, 16]
Glutamate receptors (R)
Post-synaptic membrane
-
[17]
via AMPA R
Intracellular Ca2+ level
+
[18]
Glu R2 phosphorylation
+
[18]
Post-synaptic membrane
-
[17]
R trafficking towards extrasynaptic space
+
[19]
Density
-
[20-23]
-
[17]
+
[19]
+/-
[27, 28, 30]
Membrane potential
-
[29]
AP initiation treshold
-
[29]
AP frequency
+
[29]
LTP
-
[31, 33]
LTD
+
[32, 34]
Network communication
Synchronization
+
[35]
Network excitability
Nav1.1 subunit of Na+ channel expression
-
[36]
Theta-gamma cross-frequency
Oscillation coupling
-
[43]
Neuronal level
via NMDA R
Dendritic spine
α7 nAChR
Signaling via Ca
NR2B
Endocytosis
Neuronal excitability
2+
2+
Intracellular Ca level
Neuronal circuit and network levels
Synaptic plasticity
boring neurons [47]. Astrocytes are located primarily in the
nerve fiber layer. In addition to fulfilling some of the same
roles as Müller cells [48], astrocytes play a critical role in
cell communication at the tripartite synapse (the latter involves astrocytes in addition to pre- and post-synaptic terminals which are the constituents of the classical, bipartite synapse) [49]. In contrast to Müller cells and astrocytes, which
together with neurons constitute the population of excitable
cells of the retina, microglia are classically considered as
non-excitable cells, at least in the brain [50]. However, this
concept has been challenged [51]. Microglia are located
throughout the retina and the main physiological role is to
survey the retinal microenvironment. In pathological conditions, microglia can mount a local immune response and
undertake a macrophage function after injury, such as cleaning up debris and removing dead neurons [52].
The main physiological function of the retina is to convert a visual scene into a diverse set of electrical signals and
relay these signals to the brain along the optic nerve. This
function is achieved by retinal neurons through a number of
complex signal processing operations to be discussed below
[53].
2.1. Retinal Neurons
The vertebrate retina contains complex networks of neuronal circuitry, which can be divided into three layers of neuronal cell bodies and two layers of synapses. The neuronal
layers contain the somas of five types of neurons: i) photoreceptor cell bodies are arranged into the outer nuclear layer;
ii) horizontal, bipolar and amacrine cell bodies are located in
the inner nuclear layer, and iii) ganglion cell bodies constitute the ganglion cell layer (Fig. 1). Photoreceptors, bipolar
and ganglion cells are glutamatergic neurons, whereas horizontal and amacrine cells are inhibitory neurons using,
GABA as a principal neurotransmitter [54-56]. The neurons
extend axonal and dendritic processes into the two synaptic
layers (inner and outer plexiform layers) where they connect
to each other synaptically (Fig. 1). Such spatial organization
is optimized to provide the physiological output of the retina
in the form of action potentials.
Photoreceptors are the sensory neurons responsible for
the light detection and its conversion to an electrophysiological signal, which is transmitted to their post-synaptic
partners. There are two types of photoreceptors, rod and cone
photoreceptors, in the outer nuclear layer. Rods mediate scotopic (dim) vision, and cones mediate photopic (bright) vi-
Seeing Early Signs of Alzheimer’s Disease
Current Alzheimer Research, 2017, Vol. 14, No. 1
5
sion. Rods outnumber cones by a ratio of 20:1 [57]. Cones
are concentrated in a specific region of the retina known as
macula. All photoreceptors contain a light-sensitive photopigment which triggers a phototransduction cascade in
which the light stimulus is transduced into an electrical signal [58] resulting in hyperpolarization of the photoreceptor
membrane potential. Hyperpolarization reduces the amount
of the excitatory neurotransmitter glutamate that the photoreceptors release into the synaptic space. In the dark, photoreceptors are depolarized and steadily release glutamate [59].
Horizontal cells are synaptically connected to photoreceptors and their main function is to measure the intensity of
the synaptic output from the photoreceptors and control their
excitability [60]. In addition, horizontal cells receive signals
from laterally-placed, surrounding photoreceptors and provide inhibitory feedback signals to centrally-located photoreceptors through a process known as lateral inhibition [6164].
Similar to horizontal cells, bipolar cells also receive direct synaptic input from rod and cone photoreceptors along
with some modifying input from horizontal cells in the outer
plexiform layer [65] (Fig. 1). Bipolar cells further transmit to
ganglion cells the visual signal received from each individual
photoreceptor after specific processing [66]. Each type of
bipolar cell has unique morphological and neurochemical
properties as well as unique response properties [67] that are
determined principally by the type of neurotransmitter receptors and ion channels expressed. Bipolar cells fall into two
general categories, ON and OFF, based on their respective
responses to light. ON bipolar cells express mGluR6 glutamate receptors which, upon glutamate binding, trigger closing of TRPM1 channels [68] and inhibit neurotransmission.
When the photoreceptor membrane is hyperpolarized by
light, less glutamate is released into the synaptic cleft between photoreceptor and ON bipolar cells. ON bipolar cells,
which receive less glutamate from the relevant photoreceptor, will therefore have fewer mGluR6 receptors bound by
glutamate. Consequently, bipolar cell neurotransmission is
less inhibited which results in increased depolarization and
subsequent activation of ON bipolar cells. OFF bipolar cells
express AMPA and kainite glutamate receptors [69-71]. Engagement of AMPA and kainate receptors (which are both
cation channels) by glutamate yields the rapid depolarization
of OFF bipolar cells. When the photoreceptor membrane is
hyperpolarized by light, less glutamate is released into the
synaptic cleft between the photoreceptor and the bipolar OFF
cells. Decreased glutamate release results in the opposite
response of the OFF bipolar cells (as compared to the ON
cells), i.e. an increase in the hyperpolarization (less depolarization) of the OFF bipolar cells.
Fig. (1). Schematic diagram of the mammalian retina. In the three
neuronal layers are the cell bodies of five major types of neurons:
photoreceptors (1), horizontal cells (2), bipolar cells, amacrine cells
(3), and ganglion cells. Two subtypes of bipolar cell are depicted:
ON (4) and OFF (5) bipolar cells, along with two subtypes of ganglion cell: ON (6) and OFF (7) ganglion cells. The neurons extend
their axonal and dendritic processes into the two synaptic layers
where they make synaptic connections with each other.
In this simplified scheme of ON and OFF pathways, part of the
retina is exposed to a light stimulus (area under the white bar) while
another part of the retina is dark (area under the gray bar). Depolarized neurons in the ON pathway are red, and hyperpolarized neurons in the OFF pathway are blue. For clarity, only a few bipolar
cells of each class are colored and shown connecting to ganglion
cells. A horizontal cell provides inhibitory input to a photoreceptor
synaptic terminal. Arrows indicate the direction of the flow of the
signal, and ‘+’ and ‘-‘ indicate excitatory or inhibitory polarity.
Abbreviations: ONL, outer nuclear layer; OPL, outer plexifom
layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL
ganglion cell layer.
Ganglion cells are distinguished by their unique molecular identities, response properties, and central projections
[72-74]. There are about 20 different types of ganglion cells.
Each type has a specific preferred feature to which it is optimally responsive [72]. For example, a specific ganglion cell
type receives ON and OFF components transmitted by specific ON and OFF bipolar cells. The ON- and OFF- components of the initial signal generated by the photoreceptor is
integrated by the ganglion cells which compare the incoming
ON- and OFF- inputs from the bipolar cells [63]. The visual
signal is integrated by ganglion cells to yield action potentials that are transmitted along the axons, which ultimately
come together and form the optic nerve. The axons of ganglion cells form the nerve fiber layer, which exits the back of
the eye.
Amacrine cells, which have their somas located in the inner nuclear layer, make synaptic contacts with bipolar and
ganglion cells in the inner plexiform layer. This layer is
stratified, and specific types of ganglion cells make selective
connections to bipolar and amacrine cells in each strata or
sub-layer [75]. Because the axon terminals of specific types
6 Current Alzheimer Research, 2017, Vol. 14, No. 1
of bipolar cells terminate in strata unique to each bipolar cell
type, the connections that ganglion cells make with these
bipolar cells shape the ganglion cells' response properties
[76]. For example, ON ganglion cells receive input from
light-depolarizing bipolar cells in the inner portion of the
inner plexiform layer, and OFF ganglion cells receive input
from hyperpolarizing bipolar cells in the outer portion of the
inner plexiform layer. In the inner plexiform layer, amacrine
cells provide inhibitory signals received from surrounding
bipolar cells to central bipolar cells just as horizontal cells
provide inhibitory signals received from surrounding photoreceptors [77, 78]. The major function of the amacrine cells
is therefore the “context” detection. This means that, by receiving information from bipolar cells as well as receiving
feedback from other amacrine cells, amacrine cells “sense”
the global state of activity of the entire set of the neurons that
respond to a given light stimulus.
Obviously, such a complex processing of visual information requires highly orchestrated communication between the
retinal neurons at all levels of organization (synapses, circuits and networks).
2.2. Probing Retinal Neuronal Function
Retinal ganglion cells transmit visual information from
the retina to the brain by the firing of action potentials. This
bioelectrical activity is detectable in vitro by classical methods of electrophysiology such as patch-clamp recording (at
the cellular level) and field potential recording (at the level
of neuronal populations). In addition, the global output of the
electrophysiological activity of the retina can be monitored
in vivo by electroretinogram (ERG).
2.2.1. Cellular Electrophysiology
The electrophysiological activity in the retina has been
extensively studied at the cellular level (more than 2000 citations for “retina cellular electrophysiology” since the first
recordings performed in 1950-ies). By contrast, there are
only a limited number of studies on the mechanisms individual neurons use to communicate, or in other words, how neuronal activities organize in network wiring patterns [79]. In
this context, synchronization of retinal neuronal activity can
be considered as an output of communication between distinct neurons or a group of neurons (neuronal circuits). Synchronized firing has been extensively documented in retinal
ganglion cells, however the extent and purpose are poorly
understood [80]. While little is known about the contribution
of synchronized retinal neuronal firing to the coding of visual information, some exploratory studies have shown that
synchronized firing can encode information about the presence and direction of certain kinds of motion [80, 81]. Of
note, and as a specificity of spatial organization of retinal
neurons, ganglion cells can undergo electrical coupling with
amacrine cells via gap junctions. Synaptic input from both
bipolar and amacrine cells, in combination with coupling of
ganglion cells and amacrine cells via gap junction, contributes to the synchronized firing [80, 82] of retinal ganglion
cells under certain stimulus conditions [80].
2.2.2. Electroretinogram (ERG)
The ERG is a diagnostic tool used to investigate functional changes in the retina. Several types of ERG have been
Reed et al.
developed. The full-field flash ERG, for example, is the basic method [83] for measuring the massed bioelectrical response of the retina, and it can isolate contributions of various parts of the retina. Another type of ERG, the pattern
ERG, stimulates the retina with patterned stimuli such as
reversing checkerboards and can isolate the activity of different components of the retina including the firing of ganglion cells [84].
The stimulus for the flash ERG is usually a full-field
flash of light of certain duration that covers the entire visual
field. Since the discovery of the flash ERG in the 19th century, a series of four component waves: a, b, c, and d arising
from different processes and locations in the retina have
been described. The a-wave follows the onset of the stimulus
and is generated by the photoreceptors. Immediately following the a-wave is the b-wave, arising from the bipolar and
Müller cells of the inner retina. The amplitude of the waves
indicates the health of the part of the retina from which they
originate [85]. The c wave is generated by the retinal pigment epithelium due to an increase of the trans-epithelial
potential by the light-induced bioelectrical activity of photoreceptors. This wave gives insights into the function of
epithelial cells and photoreceptors [83].
In 1999, a variant of the full-field flash ERG was developed to provide an objective method to measure the relationship between the function and the integrity of retinal ganglion cells. This variant is designated as the photopic negative response (PhNR). PhNR is a slow corneal negative potential arising after the b-wave of the standard photopic ERG
[86, 87].
The scotopic threshold response is another variant of the
full-field flash ERG in which dim (scotopic) stimuli are applied to the retina under dark-adapted conditions. Because
scotopic vision is mediated by rods, this ERG variant provides insight specifically into rod function. It is a threshold
response because it occurs near the threshold of detection for
rods [86, 88].
Importantly, certain types of synchronized activity can be
observed in the ERG. For example, the synchronous activity
of networked amacrine cells is believed to be a source of
oscillatory potentials, voltage fluctuations sometimes observed climbing the rising arc of the ERG b-wave [82, 8992].
2.3. Summary of Retinal Function
The vertebrate retina is the sensory tissue that lines the
back of the eye. Through a number of complex signal processing operations, the retina converts a visual scene into a
diverse set of electrical signals and relays them to the brain
along the optic nerve.
The retina contains six classes of neurons. In the outer
nuclear layer, the photoreceptors transduce the visual stimulus into an electrical signal. Horizontal cells, whose cell bodies are in the inner nuclear layer, mediate lateral interactions
between the photoreceptors and bipolar cells in the outer
plexiform layer. Bipolar cells transfer the visual signal vertically to the inner plexiform layer. Amacrine cells provide
vertical and additional lateral interactions in the inner plexiform layer. Ganglion cells integrate the signal and transfer it
Seeing Early Signs of Alzheimer’s Disease
along the optic nerve to the brain in the form of action potentials.
The output of the retina is in the form of action potentials
generated by retinal ganglion cells. The waveforms that
make up the ERG can be isolated to show the contributions
of various cell types and layers of the retina.
3. RETINA AND ALZHEIMER’S DISEASE
According to the classical point of view, AD pathology
leads to progressive neurodegeneration, which affects primarily the brain areas involved in cognition such as hippocampus and entorhinal cortex. Visual functions have been
considered as relatively spared until late stages of AD. Indeed, routine ophthalmologic examination of AD eyes points
to a normal appearance of retina [2]. From the clinical point
of view, psychophysical testing has shown that color vision,
visual field impairments, contrast sensitivity, depth and motion perception are all altered in advanced stages of AD (for
[2]. Consistently, longitudinal studies of normal aging have
pointed to a link between decline in visual acuity and cognitive capacities [93]. In an inverse approach, it has been
shown that in neurologically normal elderly subjects, poor
vision has a predictive value for development of dementia
[94]. Taken together, these clinical data indicate that visual
deficiencies may be a part of the clinical panel of symptoms
in advanced stages of AD. This consensus is further supported by the fact that a number of AD-related alterations in
the eye, including retinal changes and optic nerve fiber thinning, have also been identified in advanced AD [95-97].
However, recent research suggests that at the early stages
of disease, non-cognitive functions, including visual perception and processing, may also be affected.
3.1. AD-Related Changes in the Retina
Both intracellular and extracellular accumulation of the
proteins (hyperphosphorylated tau and Aβ) have been reported in the retina. The ectopic accumulation of these proteins is associated with significant structural changes of the
retina and optic nerve although these alterations are mainly
detectable only when pathology has significantly progressed.
3.1.1. Aβ Plaques and Neurofibriallry Tangles
Aβ plaques and neurofibriallry tangles have been identified in the retina in advanced stages of the disease both in
AD mouse models [98-100] and in post-mortem human retina from AD patients [101]. At least in mice, neurofibrillary
tangles and Aβ plaques spread along all layers of the retina
as in Tg2576 mice [102, 103]. By contrast, in APP/PS1 double transgenic mice most of Aβ plaques were preferentially
found in the ganglion cell layer and inner plexiform layer
[102, 104]. However, in all AD mouse strains studied, the
accumulation of retinal Aβ plaques was age-dependent, as
detected in the human brain [105].
Some strains of AD mutant mice undergo the accumulation of intracellular Aβ within retinal ganglion cells as well
as inner and outer nuclear layers of the retina [106]. Most
importantly, the recent study using hyperspectral imaging
has shown that they are detectable in the retina of APP/PS1
mice during the asymptomatic stage of AD [107]. The as-
Current Alzheimer Research, 2017, Vol. 14, No. 1
7
ymptomatic stage refers to the preclinical phase in human
pathology which progresses insidiously from amyloidosis
with soluble Aβ oligomers alone (stage 1), amyloidosis
combined with neuronal damage (stage 2) up to the subtle
cognitive decline, undetectable by standard tests (stage3).
The asymptomatic stages precede the clinical stage, characterized by mild, but clinically detectable, cognitive impairment (MCI) and biomarker evidence for AD. The final, more
advanced stage is defined in humans as dementia due to AD
[108]. Therefore, the detection of soluble Aβ oligomers in
mouse retina would correspond to the stage 1 of the preclinical phase which occurs a few months before Aβ plaques are
detectable This is a crucial finding since the soluble Aβ oligomers, rather than Aβ plaques, are currently considered the
main Aβ toxic species [109, 110]. Soluble oligomers accumulate at synapses yielding impairment in synaptic plasticity
and memory before Aβ is deposited in plaques and before
neurodegeneration is detectable [111]. The data obtained
using the new hyperspectral imaging technology for retina
exploration strongly suggest that early Aβ-related synaptic
alterations may begin in the retina during the asymptomatic
stage.
3.1.2. Structural Changes of the Retina and Optic Nerve
The thinning of the retinal neurofibrillary layer, which
contains the axons of the ganglion cells which form the optic
nerve, has been repeatedly demonstrated in advanced AD [2]
and is correlated with a decrease in the density of optic nerve
fibers [96, 112]. The neurofibrillary layer thinning is combined with reduction of macula thickness/volume, which is
in turn correlated with the degree of cognitive impairment in
advanced AD [113].
In the early stages of AD, spectral domain optical coherence tomography (SD-OCT) techniques have detected neurofibrillary layer degeneration in MCI (mild cognitive impairment) [114]. SD-OCT is a non-invasive, non-contact
method that allows for a precise and quantitative assessment
of retinal morphology with longitudinal, reproducible follow-up. At the cellular level, the thinning of the neurofibrillary layer is accompanied by a loss of ganglion cell neurons
[115, 116]. Most importantly, ganglion cell loss is preceded
by dendritic atrophy of these neurons, which, in addition,
precedes significant dendritic degeneration in hippocampal
pyramidal neurons in Tg2576 mice with overt AD pathology
[117]. However, photoreceptor neuronal death has not been
observed in the advanced stages of AD pathology in a mouse
AD model [118].
It has to be stressed that even if the older studies failed to
detect early alterations ([119] - for retinal neurofibrillary
layer; [120] and [121] - for ganglion cell loss), recent studies
using more sophisticated technology, report degenerative
changes (thinning of the specific retina regions, loss of optic
nerve fibres and ganglion cells), that appear concomitantly
with the early cognitive deficits [114].
3.2. ERG and Electrophysiology of Retinal Changes in
Alzheimer’s Disease
Alterations in bioelectrical response of the AD eye to
light stimulation have been documented by different types of
8 Current Alzheimer Research, 2017, Vol. 14, No. 1
ERG: full-field ERG, pattern ERG (PERG) and multifocal
ERG.
3.2.1. ERG
Full-field flash ERG has been studied in AD patients under both scotopic and phototopic conditions. The majority of
studies did not detect significant differences between patients and age-matched normal subjects [2, 122-124].
By contrast, scotopic full-field flash ERG studies in animal AD models, such as aged APP/PS1, have reported a decrease in the amplitude of a- and b- waves in advanced
stages of pathology as compared to non-transgenic littermates [118]. Shimazawa and colleagues provided evidence
that increased latency to each peak, after light stimulus, in
ERG recordings in Tg2576 and APP/PS1 mice correlate with
lower expression levels of the NR2B subunits of NMDA
receptors [106]. Based on these finding, the authors postulated that Aβ may impinge on retinal function by impairing
NMDA signaling pathways [106], as detected in the vulnerable brain areas [17, 19] (see also the section 1.3.1). Remarkably, it was published this year that subretinal injection
of Aβ in C57/BL6 mice yields declined scotopic response
[125].
Initial PERG studies of AD retinas failed to detect significant differences between patients and age-matched controls [119,123,126]. However, more recent studies reported
significant alterations in amplitude of the positive component peaking at 50 ms (P50) combined with a P50 increase in
latency [127-129] or not [130-132].
To sum up, the recent PERG studies using more advanced technology have reported alterations that are suggestive of ganglion cell dysfunction. In animal models, full-field
flash ERG a- and b-waves were reduced under scotopic but
not photopic conditions (Table 2). However, it should be
kept in mind that basic full-field flash ERGs measured in
response to a flash of light detect damage only when there is
Table 2.
Reed et al.
a significant loss in the number of retinal neurons. More sensitive methods are needed to detect alterations earlier in the
progression of the disease.
3.2.2. Cellular Electrophysiology of Retinal Cells in AD
To the best of our knowledge, there is so far not a single
study performed in the retina of AD mouse models using
cellular electrophysiology.
4. NEW AVENUES FOR REVEALING THE EARLIEST AD BIOMARKERS BY ELECTROPHYSIOLOGICAL EXPLORATION OF THE RETINA?
As already discussed in section 3 of this review, visual
disturbances are among the complaints reported by AD patients [132]. Furthermore, as in the brain, during the overt
stage of AD pathology, Aβ plaques are detectable in the retina ([101]; see section 3.1.1) as well as functional changes in
ERG recordings ([130]; see section 3.2.1). Importantly,
changes in the retina are also detectable at early stages of
AD. For example, imaging the retinal nerve fiber layer using
SD-OCT showed that retinal neurofibrillary layer thickness
was significantly decreased in patients with MCI compared
to controls ([114] and section 3.1.2). In this light, some exciting technological achievements have been accomplished
lately. Among them, the methodology such as fluorescence
lifetime imaging ophthalmoscopy (FLIO) will certainly become a valuable diagnostic tool. FLIO is based on scanning
laser ophtalmoscope using excitation pulse, which yields
autofluorescence that is readily detectable in the retina. The
comparative pilot study published at the end of the last year
with a cohort of 16 patients diagnosed as early AD has convincingly demonstrated that FLIO, but not conventional
OCT, could reveal significant correlation with the cognitive
status (MMSE score) and phospho-tau levels in the CSF
[133]. These findings support the possibility of using the
retina as a surrogate for detection of early pathological
changes in the brain and point to the exiting possibility of
Electrophysiological alterations in AD retina.
Methodology
Type of alteration
Species / Model
References
Full-field
(scotopic and phototopic)
No alteration
Human
[2, 122-124]
Full-field
(scotopic)
Decreased a & b waves
Mouse, APP/PS1deltaE9
[118]
Full-field
(scotopic)
Decreased a & b waves
Mouse, C57/BL6
[125]
Full-field
(phototopic)
Increased peak latency after light stimulation
Mouse, Tg2576
No alteration
Human
[119, 123, 126]
Increased P50 peak & P50 latency
Human
[127-129]
No increase in P50 latency
Human
[130-132]
ERG
(retinal Aβ injection)
[106]
PERG
Seeing Early Signs of Alzheimer’s Disease
Current Alzheimer Research, 2017, Vol. 14, No. 1
9
identifying these alterations by non-invasive modern imaging such as laser scanning ophtalmoscopy.
after a systematic exploration using more advanced technology.
In addition to the structural changes detectable by noninvasive imaging methodologies, the functional prodromal
changes in neuronal excitability may also be detectable in the
retina, which could serve as a biomarker for early diagnostic
purposes [1]. The relevance of the search for the earliest
electrophysiological AD-associated alterations in the retina
is further strengthened by the fact that, at least in the brain,
the Aβ-related impairment of synaptic transmission [17,30]
precedes destabilization of neuronal network activity and
induction of aberrant network synchronization ([35,43]; see
also 1.3.2). Indeed, synaptic loss is one of the first functional
hallmarks of AD and is the best correlate of cognitive decline [3]. ERG evaluation of synaptic function has been very
recently validated for use in the mouse retina [134]. Relevantly, the latter study has also reported that mice carrying
the ApoE-ε4 allele of apolipoproteine E4, the most prevalent
genetic risk factor for the late-onset AD, which acts in synergy with Aβ, present a significant reduction in mixed rodcone responses, such as decreased a- and b-wave amplitudes
[134]. Thus two of the hallmark characteristics of AD lead to
changes in retinal function in rodent models.
Because retina is a window to the brain, which can be
explored non-invasively, and because new data has convincingly shown that AD pathology likely begins in the retina
prior to the brain (section 3.1.1), it is sound to search for the
earliest AD diagnostic markers in retina. We believe that
exploring the retinal neurons by both advanced laser imaging
methodologies and future, more sensitive retinal electrophysiology devices, would help identifying the first Aβrelated structural and functional alterations in the retina. During the last years, a tremendous progress has been accomplished in developing laser-based non-invasive imaging
technologies. The same efforts should be now made to develop more advanced modalities of ERG. To achieve this
goal, researchers, ophthalmologists and physicists should
work hand-in-hand. The next-generation tools for monitoring
the activity of the cell types, identified by cellular electrophysiology, exhibiting altered synaptic activity, will likely
help establish AD diagnosis much earlier than currently possible. For example, if cellular electrophysiology identifies
amacrine cells as the specific type of neuron displaying altered synaptic activity during the asymptomatic stage of AD,
then development of more sensitive devices recording negative oscillatory potential for use in human, will undoubtedly
be a big step towards earlier AD diagnosis.
Finally, using electrophysiological exploration of the retina (ERG), instead of brain (EEG) holds a significant advantage. Indeed, it has been reported that modern EEG can be
used to detect cross-frequency uncoupling in hippocampus
[43, 44]. However, EEG recording of cross-frequency uncoupling in hippocampus is unlikely to become an early diagnostic marker since detection remains challenging because
the hippocampus is a relatively deep brain structure. One
option would be to transpose the search for diagnostic markers from the brain to the retina, which is a part nervous system and is amenable to non-invasive and uncostly study by
using a totally safe ERG exploration [1].
CONCLUSION AND FUTURE DIRECTIONS
In spite of the accumulating body of evidence that early
disturbances in visual function in AD involve alterations
within the retina, some evidence is still elusive or even contradictory. For example, in AD patients, no significant difference was seen in ERG studies (section 3.2.1). By contrast,
in animal AD models, scotopic (but not photopic) ERG response appears altered (section 3.2.1), thus suggesting possible rod photoreceptor dysfunction (although contribution of
the downstream neurons cannot be excluded). However,
structural alterations of rod photoreceptors are not detectable
and, as with cones, rods appear to be spared even at the late
stages of AD (section 3.1.2). Such inconsistencies may simply be related to the insensitivity of current methods used for
detection in humans. This statement is, for example, supported by the data obtained for another type of retinal neuron: the ganglion cell. Early studies (before 2000), using less
sophisticated devices, could not resolve the AD-related loss
of ganglion cells. However, using more elaborate methods of
detection, ganglion cell loss has been systematically found in
both AD patients and animal models, with overt pathology
(section 3.1.2). These facts strongly suggest that previous
views suggesting that the visual system (including retina and
optic nerve) is not affected in AD should be reconsidered
In conclusion, the major advantages of exploring retina
as the source of the earliest AD biomarkers are that it can be
studied intact and non-invasively which make the eye suitable for analysis with low-cost and widely available devices
such as the more advanced ERG. This goal is among the
major challenges for the future, in the light of the everincreasing proportion of the elderly population world-wide
and that AD has recently met the World Health Organization’s criteria of “epidemic” disease. At the individual level,
achieving this goal will allow all of us to reach old age with
the knowledge that moving the borders of the onset and progression of diseases like AD sufficiently far away will improve our quality of life.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
We thank our young colleagues, Aileen Hofer and Matthieu Capelo for constructive discussions. We would also
like to acknowledge the support from Fondation pour la Recherche Médicale (operating grant FRM n°DVS
20131228910 to SK) and from Région Ile-de-France (DIM
Cerveau et pensée to SK).
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