Download Human brain amyloidoses.

Nephrol Dial Transplant (1998) 13 [Suppl 7]: 33–40
Nephrology
Dialysis
Transplantation
Human brain amyloidoses
P. Gambetti and C. Russo
Institute of Pathology, Division of Neuropathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland,
Ohio 44106, USA
Introduction
Several diseases affecting the central nervous system
(CNS) of humans result from the formation
of a substance, named amyloid. Amyloid currently
identifies aggregates of an insoluble protein which
(i) generally occupy the extracellular space, (ii) are
birefringent under polarized light, (iii) react with the
Congo red histological stain, (iv) have a ß-pleated
sheet secondary structure, (v) are fibrillary with an
extensive antiparallel b-sheet strands quaternary structure, and (vi) are associated with other proteins presumed to be chaperones [1]. At least five biochemically
distinct amyloids are known to affect the human CNS
( Table 1). The amyloidoses due to the aggregation of
the amyloid b peptide (Ab), which include Alzheimer’s
disease (AD), Down’s syndrome (DS) and the
hereditary cerebral haemorrhage with amyloidosis
(HCHWA)-Dutch type, and the amyloidoses due to
aggregation of the prion protein (PrP), which include
the Gerstmann–Sträussler–Scheinker disease (GSS),
some variants of the Creutzfeldt–Jakob disease (CJD)
and Kuru, are by far the most common. However,
amyloidomas and transthyretin amyloidosis have also
been reported. Recent advances in the understanding
of neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s
disease, and several forms of complex systemic degenerations, point to an amyloidogenic process as the
central event in the pathogenesis of these diseases
Table 1. Amyloidoses of the central nervous system
Disease
Amyloid
Amyloidomas
Oculoleptomeningeal A
Meningocerebrovascular A
Alzheimer’s disease
Down’s syndrome
HCHWAa-Dutch type
HCHWAa-Icelandic type
Transmissible spongiform
encephalopathy
Multiple myeloma-associated AL
Transthyretin
Transthyretin
Amyloid b protein
Amyloid b protein
Amyloid b protein
Cystatin C
Prion protein
aHereditary cerebral haemorrhage with amyloidosis.
[2–5]. Therefore, the chapter of the human brain
amyloidoses is likely to expand and to include many
degenerative diseases of the nervous system in the
near future.
This review summarizes the salient clinical and
pathological features of the brain amyloidoses with
special emphasis on the data obtained by our group.
Some of the mechanisms involved in the pathogenesis
of AD and prion disease are also briefly discussed.
Brain amyloidomas
Amyloid may deposit in the brain in the form of
relatively large aggregates acting like space-occupying
lesions, called amyloidomas [6–16 ]. Twelve cases have
been reported to date ( Table 2). The mean age at
presentation is 54 years (range 28–76 years). The
common clinical presentation is characterized by cognitive decline, seizures and signs of increased intracranial pressure. One case remained asymptomatic [10].
The location within the brain is variable but it is most
commonly supratentorial and it involves the frontal
and occipital lobes. In one case, the amyloidomas were
located in the cerebellum and pons [11]. The amyloidomas may be single or multiple and present sizes that
may vary between 0.5 and 8 cm in diameter. In the
subject observed by us, the amyloidomas formed nodular masses of variable sizes far in excess of those
detected with the magnetic resonance imaging (MRI )
examination [11]. The amyloidomas were surrounded
by cells identified as microglia which often showed
intimate contact with the amyloid through digitating
processes projecting into the amyloidoma [11]. Plasma
cells were often seen around but not in contact with
the amyloid. Immunocytochemistry indicated that the
plasma cells contained l light chains, and immunoelectrophoresis of the cerebrospinal fluid (CSF )
demonstrated a monoclonal IgG-l with free l light
chains, consistent with the presence of an aberrant
clone of plasma cells within the CNS [11].
Immunohistochemistry as well as amino acid sequence
analysis of amyloid fibrils purified from the amyloidomas demonstrated that the amyloid protein is an
unusual immunoglobulin l light chain, starting at
© 1998 European Renal Association–European Dialysis and Transplant Association
34
P. Gambetti and C. Russo
Table 2. Intraparenchymal amyloidomas
Case
Age
(yr)
Presentation
Location
Amyloid
type
Saltykow [6 ]
Harris and Rayport [7]
Spaar et al. [8]
Townsend et al. [9]
Case 1
Case 2
Hori et al. [10]
Cohen et al. [11]
NR
28
46
Psychiatric
Focal seizures
Visual loss
Cortex and white matter
Frontal white matter
Occipital white matter
ND
ND
ND
47
50
60
32
76
58
61
Frontal white matter
Occipital white matter
Occipital white matter, basal ganglia
Extensive white matter, including left
frontal, left cerebellum, pons
Right parietal
Frontal white matter
Parietal white matter
ND
ND
ND
AL
Eriksson et al. [12]
Linke et al. [13]
Lee et al. [14]
AL
AL
ND
Schroeder et al. [15]
Caerts et al. [16 ]
70
71
Cognitive decline
Visual field defect
Asymptomatic
Headaches, seizures, optic disk swelling,
dementia
Seizures
Multiple sclerosis-like
Mental deterioration
Seizures
Hemiparesis, hemiataxia, decreased attention
Hemiparesis
Right parieto-occipital region
Lateral ventricle above thalamus
AL
ND
NR, not recorded.
residue five of the variable domain [17]. The amyloid
protein had a mol. wt of 10–30 kDa. The higher
molecular weights probably arose from the polymerization of the 10 kDa subunit or sequential proteolytic
cleavage of the light chain, or both [17]. Together,
these data indicate that the amyloidomas in our observation contain primary myeloma-related amyloid (AL)
which is most likely the product of an amyloidogenic
plasmacytoma of the brain. This was the first identification of the protein component of a brain amyloidoma. AL amyloid has been found in subsequent
cases of brain amyloidomas, suggesting that it may be
the component of most if not all brain amyloidomas
[12,13,15].
Transthyretin amyloidosis of the central nervous
system
Autosomal dominant mutations in the gene of the
plasma protein transthyretin ( TTR), previously called
pre-albumin, account for the majority of the human
familial amyloidoses [18]. Over 60 distinct mutations
resulting either in single or double amino acid substitutions have been reported [19–21]. By far the most
common phenotype associated with mutations in the
TTR gene is a condition identified as familial amyloidotic polyneuropathy [23]. Involvement of the CNS
in TTR amyloidosis is very rare. Eight distinct mutations of the TTR gene have been reported to be
associated with a familial amyloidosis which is characterized by amyloid deposition predominantly in the
CNS and its coverings [22]. This disease entity has
been designated familial oculoleptomeningeal amyloidosis when the eye is also affected, or meningocerebrovascular amyloidosis when there is no eye
involvement ( Table 3) [23–25]. The involvement in
most of these mutations is limited to the meninges,
dura mater and/or leptomeninges and their vessels as
well as the vessels of the brain, especially those at the
or near to the surfaces (Table 3). Amyloid deposits in
the brain parenchyma have been observed in only three
TTR gene mutations. We had the opportunity to
identify one of these three mutations, a point mutation
resulting in the substitution of valine with glycine, and
to study the disease phenotype in one affected kindred
[22]. Clinically, the distinctive characteristics in this
kindred are episodes of progressive motor deficits such
as hemiparesis and ataxia, associated with progressive
cognitive impairment, abnormal behaviour, seizures
and headache. Decreased vision due to vitreous opacities is almost invariably present. Histopathologically,
the hallmark is the presence of TTR amyloid deposits
in the subependymal region, in the leptomeninges and
in the wall of the subarachnoid blood vessels. The
subependymal amyloid deposits are associated with a
glial reaction resulting in the alteration of the ventricular wall and narrowing of the ventricular lumen, especially at the level of the aqueduct. The meningeal and
vascular deposits are likely to be the cause of the
multiple infarcts and hypoxic–ischaemic changes present in virtually the entire CNS. In contrast, amyloid
deposits in the peripheral nerves are rare. Small amyloid deposits are present in the retina and retinal vessels.
The peripheral nerves are minimally affected. Clinical
and pathological features similar to those of the present
kindred have been observed in other kindreds reported
under the label of oculoleptomeningeal amyloidosis
[26–29]. However, the nature of the amyloid and the
presence of a mutation in the TTR gene have not been
established in these families. Recently, a Hungarian
kindred carrying a mutation in the TTR gene resulting
in the replacement of asparagine with glycine (D18G)
has been reported [30]. Clinically, affected subjects are
reported to have memory loss, decreased hearing, signs
of cerebellar and pyramidal dysfunction with episodic
confusion and hallucinations. Pathologically, TTR
amyloid deposits were observed in ‘meningeal vessels
and subpial areas’; however, no other details are
given [30].
Human brain amyloidoses
35
Table 3.
Mutation
18Gly
(1)
30Met
(2)
55Pro
(3)
60Ala
(4, 5)
70Asn
(6)
114Cys
(7)
6Ser
54Gly
(8)
FOA
(9)
30Gly
(10)
Meninges
CNS parenchyma
PNS
Eye
Other organs
+/
/+a
++
+/+
+/+
+
+/−
++
++
++
+
−
++
++
−
+/++
+
+/−
++
−
+
+/−
++
+
++/+
+/−
+
+/+
+/++
++/+
+/−c
+/−
+/+
+++/−
++/++
++
+/+
Value on left of slash refers to vessels; value on right to parenchyma; no slash indicates no vascular or parenchyma location specified.
aLimited to the subpial region; blimited to the subependymal and subpial regions; FOA, familial oculoleptomeningeal amyloidosis; CNS
and PNS, central and peripheral nervous system respectively; −, amyloid not present; +, present amount unspecified; ++, present in
large amounts; (1) Vidal R et al. Am J Pathol 1996; 148: 361–366; (2) Benson MD et al. Ann Intern Med 1977; 86: 419–424; (3) Jacobson
DR et al. Hum Genet 1992; 889: 353–356; (4) Koeppen AH et al. Muscle Nerve 1990; 13: 1065–1075; (5) Koeppen AH et al. Muscle Nerve
1985; 8: 733–749; (6) Izumoto S et al. Neurology 1992; 42: 2094–2102; (7) Ueno S et al. Brain 1992; 115: 1275–1289; (8) Reilly MM, Brain
1995; 118: 849–856; (9) Uitti RJ et al. Arch Neurol 1988; 45: 1118–1122; (10) Petersen RB et al. Ann Neurol 1997; 41: 307–313.
The mechanism leading to the involvement of the
CNS parenchyma, blood vessels and intracranial meninges, as opposed to the peripheral nervous system
(PNS), in TTR amyloidosis remains obscure. The
TTR molecule has an extensive b structure. The TTR
monomer has eight b-chains arranged in antiparallel
configuration in two planes [19]. Such a configuration
is likely to predispose the TTR molecule to aggregate
and form amyloid fibres as a result of a destabilizing
change such as the presence of a mutation [19]. The
V30M mutation, which is commonly associated with
peripheral neuropathy, causes the increase of the sheet
to sheet separation which, in turn, may result in altered
disulfide bond formation and the subsequent formation
of aggregates [31,32]. The V30A mutation as well as
the V30G mutation that we observed might also be
expected to reduce the sheet to sheet distance due to
the smaller size of the residues. It is of interest, in this
regard, that our kindred and the other kindred with
the TTR phenotype characterized by clinical and histopathological involvement of meninges and brain parenchyma are both associated with a mutation resulting
in the presence of a glycine residue in the N-terminal
region of the TTR molecule [30].
The major phenotypic difference between the affected
individuals with the V30G and those with the V30M
mutations appears to be in the clinical features more
than in the amyloid distribution. In the V30G-affected
subjects, the signs of CNS involvement are prominent
while those of PNS involvement are minimal or absent.
The opposite applies to the phenotype of the V30M
mutation. Nevertheless, amyloid deposits are present
in the peripheral nerve and in the brain and intracranial
meninges with both mutations. V30G-affected subjects
also have significant brain parenchymal damage apparently secondary to the vascular amyloidosis which has
not been observed in symptomatic V30M subjects. The
distribution of the amyloid deposits in the leptomeninges and in the wall of the ventricles is highly consistent with the notion that, contrary to the TTR of the
blood plasma that is synthesized in the liver, the TTR
present in the CSF is synthesized by the epithelium of
the choroid plexi and the vitreous TTR by the retinal
pigmented epithelium [33]. Thus, different TTR gene
mutations might selectively affect not only the amount
but also other features such as conformation, relating
to the pathogenicity of the mutant TTR molecule
synthesized in the different compartments. Whether
the clinical and pathological features of the present
kindred are due to a more abundant or more cytotoxic
mutant TTR expressed in the choroid plexi or to other
factors remains to be clarified.
Hereditary cerebral haemorrhage with
amyloidosis-Icelandic type (HCHWA)-I
HCHWA-I is an autosomal dominant disease associated with a point mutation in codon 68 of the
cystatin-C gene located in chromosome 20, resulting
in the substitution of glutamine with leucine [34]. The
cystatin C protein (CC ) is composed of 120 amino
acids with two disulfide bridges near the C-terminus.
The protein is a member of the family 2 cystatins,
which are cysteine proteinase inhibitors. The amyloid
form contains a 12 kDa truncated form of the mutant
C protein, missing the 10 N-terminal residues [34].
X-ray analysis demonstrated that the Leu68 residue is
buried in the hydrophobic core of the protein that
seems to be the proteinase-binding region. As for TTR,
the choroid plexus is considered to be the major site
of CC synthesis, and patients with HCHWA-I have
significantly lower CSF concentration of CC than
normal subjects [35]. Several families as well as individual cases from apparently asymptomatic families in
Iceland are affected [34,36,37]. The disease generally
begins in the third and fourth decades and has a
duration of ~10 years. The clinical presentation
includes cerebral haemorrhage and minor infarctions
associated with, and occasionally preceded by, cognitive impairment [34,37]. Pathologically, cystatin C
amyloid is deposited in the leptomeningeal and intraparenchymal medium and small size vessels of cerebral
grey and white matter which hyalinized and thickened
walls [37]. The cerebral parenchyma shows infarctions,
generally haemorrhagic, of various size and age.
36
P. Gambetti and C. Russo
Cystatin amyloid deposits are also present in the
superficial dermis [37].
Alzheimer’s disease and other related amyloidoses
One of the distinctive features of AD is that the
phenotype is remarkably uniform despite the multiple
aetiology of the disease. In addition to the sporadic
form in which the aetiology is unknown, the AD
phenotype is also associated with distinct genetic conditions which include the trisomy 21 or Down’s syndrome
(DS) and different familial forms of AD ( Table 4)
[38]. The presence of AD in DS is attributed to the
increased dosage of DNA, including the genomic DNA
of the ß amyloid precursor protein (ßAPP), caused by
the presence of an extra chromosome or, more rarely,
of extrachromosomal material resulting from a translocation [39]. The DNA increased dosage results in a
4- to 6-fold increase in the expression of APP [39].
Familial forms of AD are linked to numerous distinct
mutations in the ßAPP gene on chromosome 21, in
the genes of two transmembrane proteins, called
presenilin-1 and presenilin-2, which are located on the
chromosomes 14 and 1, respectively. The relative uniformity of the disease phenotype in the presence of
this aetiological diversity strongly suggests that there
a common pathogenic pathway or cascade of events
common to all these AD forms. This brief review
focuses on some early events that may lead to the
formation of the amyloid deposits and that can be
shared by all forms of AD. Several recent reviews deal
with all the other aspects of AD [38,40].
The invariable lesion and the histopathological hallmark of all forms of AD is the presence of amyloid
deposits or plaques in the parenchyma and often in
the vessels of the CNS and the leptomeninges [40]. In
most subjects, there also is a neurofibrillary degeneration of neuronal cell bodies and their processes. The
amyloid plaques are of two basic types. The so-called
mature plaques are composed of deposits with the
tentorial characteristics of the amyloid, i.e. positive
with Congo red staining and apple green birefringent
at polarized light, and with a target-like arrangement,
i.e. a core surrounded by a concentric crown
(Figure 1). The crown also contains distorted neuronal
cell processes as well as reactive glial cells. The plaques
of the second type, referred to as diffuse plaques, are
Table 4. AD genetic factors
Chromosome 21
Chromosome 21
Chromosome 19
Chromosome 14
Chromosome 1
Others (?)
Trisomy 21/Down’s
syndrome
APP gene mutations
APOE related
susceptibility
Presenilin 1 gene
mutation
Presenilin 2 gene
mutation
?
All subjects >50 years
have AD
~12 Families
16% of US population
has APOE allele
4
Majority of FAD
families
A few families
A few families
made of aggregated material that does not display the
characteristics of the amyloid and are associated with
minimal or undetectable structural alterations of the
brain parenchyma. The deposits present in the diffuse
plaques have been named pre-amyloid, implying that
the diffuse plaque is the precursor of the mature
plaques. This assumption is supported by the finding
that in the early stages of the disease the plaques are
predominantly of the diffuse type [40] and cases have
been reported in which the presence of a significant
number of diffuse plaques is asymptomatic. If the
diffuse plaques precede the mature plaques, then in
AD amyloid formation is preceded by a condition in
which the amyloidogenic protein is aggregated but
does not form ß-pleated sheets. Although these pathogenic events seem very logical and attractive, they have
not been proved definitely to date. Regardless of
whether they are in the form of amyloid or preamyloid, the deposits present in all plaques of AD
contain primarily peptides of variable length identified
as amyloid ß peptide (Aß) which, in turn, derives from
a larger protein named amyloid ß precursor protein
(APP). APP is a transmembrane glycoprotein generated in several isoforms by alternative splicing of a
single gene located on chromosome 21 (Figure 2) [38].
The Ab is an internal sequence of APP, partially
embedded in the membrane, which is thought to derive
from cleavage of APP by at least three still unidentified
proteases named secretases a, b and c [40]. Normally,
the a secretase cleaves APP between residue 16 and 17
of the Ab region. This cleavage, which probably occurs
at the membrane, results in the secretion of the APP
fragment containing the N-terminal region, whereas
the intracellular C-terminal fragment is likely to be
degraded in intracellular compartments. Intact Ab is
thought to be produced by the cleavage at its N- and
C-termini of b and c secretases, respectively. There are
several isoforms of Ab which have been demonstrated
in brains and CSF of subjects with AD [41]. Two
major Ab isoforms can be distinguished according to
whether they end at the C-terminal residue 40 or 42,
and are identified as Ab and Ab [38]. Considerable
40
42
indirect evidence has been accumulated that Ab, especially the Ab isoform, plays a critical role in the b
42
amyloid formation of AD. In addition to being the
main component of both mature and diffuse plaques,
Ab has also been found to be increased in the plasma
42
and in fibroblasts of subjects with genetic forms of
AD, and Ab in culture is secreted in increased
42
amounts by cells carrying genetic mutations associated
with AD [38]. Moreover, Ab and even more Ab
40
42
are highly amyloidogenic and neurotoxic in vitro,
probably following a change in conformation [42].
Therefore, it is believed that an increased amount of
Ab, especially Ab , is the common pathogenetic event
42
shared by all forms of AD. However, no evidence for
this has been obtained in the brain tissue.
In collaboration with Jan Teller, Massimo Tabaton
and others, we have carried out the first search on the
water-soluble Ab (sAb), i.e. Ab not stably associated
with amyloid and pre-amyloid deposits, in the brain
Human brain amyloidoses
(A)
37
(B)
Fig. 1. (A) Neuritic plaque showing numerous agryrophilic degenerating neurites forming a crown and a poorly stained core of amyloid
(silver stain). (B) The amyloid core of a neuritic plaque is intensely stained green by an amyloid stain.
Fig. 2. Diagrammatic representation of amyloid precursor protein
(APP). The cleavage sites of the a, b, and c proteases (secretases)
and the amyloid b (Ab) peptide are indicated.
parenchyma of subjects with AD, subjects with DS
and appropriate controls [43,44]. A large amount of
sAb was present in the AD brains (Figure 3). This
finding was expected since in virtually all amyloidoses
the protein forming the amyloid deposits is in equilibrium with the soluble form. The finding that sAb was
undetectable in brains free of Ab plaques was less
expected since sAb is secreted by cells in culture and
it is commonly stated that Ab is normally present in
the brain parenchyma. We then examined the presence
of sAb in the brain tissues of subjects with DS who
came to autopsy at various ages. Virtually all subjects
with DS develop AD between the age of 20 and 40
years [44]. Therefore, by examining the brain parenchyma in these subjects, one may identify changes
preceding the formation of plaques. Analyses of DS
brains showed that sAb is present in significant
amounts from birth and increases dramatically when
diffuse or mature plaques appear. In contrast, sAb was
undetectable in brains free of plaques, from agematched individuals with various pathologies (AD and
DS excluded) in 35 out of 37 cases. Therefore, the
presence of abnormal amounts of sAb precedes the
appearance of diffuse and mature plaques in DS. On
gels, sAb from either AD or DS brains separates into
three bands, indicating the presence of at least three
distinct isoforms [45]. Further characterization of sAb
showed that the upper band corresponds to the fulllength sAb made of residues 1–42 either as an unmodified form or as a form in which the aspartate residue
is racemized or isomerized; the intermediate and lowest
bands are both made of sAb isoforms containing
pyroglutamate and ending at residue 42. In these two
bands, the pyroglutamate modifies residue 3 and 11,
respectively, which are also the starting residues of
these two sAb isoforms. Moreover, the amount of the
pyroglutamate-modified sAb
appears to increase
3–42
progressively with age in DS brains. Non-denaturing
gel filtration and chromatography show that although
water-soluble, the sAb we examined is in aggregates
which include all three isoforms [45]. Finally, sAb is
apparently unrelated to the insoluble Ab since insoluble
Ab was present in similar amount in plaque-free brains
from controls, which did not contain any detectable
38
P. Gambetti and C. Russo
Fig. 3. Immunoblots of soluble Ab extracted from brains from subjects with Alzheimer’s disease (AD) and control. Three Ab isoforms are
identified in AD brains. While normal brains have no detectable soluble Ab. AP: synthetic Ab peptide.
Ab, and in plaque-free DS brains, which instead contained a significant amount of sAb [45]. Recently it
has been shown that in culture cells, sAb is processed
42
through a cellular pathway different from that of
sAb , suggesting that in DS brain, probably because
40
of overexpression of APP, the sAb -generating meta42
bolic pathway is favoured [46 ].
In conclusion, post-translationally modified forms
of sAb are abnormally present in plaque-free DS brains
which are bound to develop amyloid plaques at later
ages. This finding indicates that the presence of sAb
1–42
and its modified forms precedes and perhaps is an
essential step in the pathogenesis of amyloid plaque
formation in DS-associated AD, and perhaps in other
forms of AD.
HCHWA-Dutch type (HCHWA-D) is an autosomal
dominant disease, caused by deposition of b amyloid
in the leptomeningeal arteries and cortical arterioles,
leading to fatal strokes in the fifth or sixth decade of
life [47,48]. Only diffuse plaques are found in the
parenchyma and only in older patients is it possible
find some congophilic plaques. Amyloid angiopathy
has never been detected in spinal cord or its meninges
[49]. The disease is due to a point mutation at codon
693 of the APP gene that codifies a glutamine for a
glutamic acid at position 22 of Ab.
Prion diseases
Prion diseases, also called transmissible spongiform
encephalopathies, are fatal neurodegenerative disorders that affect humans and animals. They have the
unique characteristic of being at the same time inherited and infectious [51]. Although not yet universally
accepted, the dominant pathogenetic hypothesis, also
referred to as the prion hypothesis, postulates that the
central event shared by all forms of prion diseases is a
change in conformation resulting in the conversion of
a normal glycoprotein located mostly in the plasma
membrane, named cellular prion protein (PrPc), into
a conformer that has the same amino acid sequence
and post-translational modifications as PrPc but differs
in conformation, resistance to digestion with proteases,
and pathogenicity. Three forms of prion diseases
are commonly distinguished: inherited, sporadic and
acquired ( Table 5). According to the prion hypothesis
[50], the change in conformation of PrPc into PrPres,
would be (i) an almost invariable consequence of
the instability of PrP in the presence of a mutation
in the familial or inherited form, (ii) the result of a
spontaneous, random event in the sporadic form; or
(iii) induced by the exposure to exogenous PrPres in
the prion diseases transmitted by infection. The propagation of the disease would occur through the interaction between PrPc and PrPres. The PrPres acting as a
template would convert the PrPc molecule into another
PrPres molecule. The dissociation of the complex would
then release the previously formed and the newly
formed PrPres molecules, which would continue the
conversion process in an autocatalytic chain reaction
[51]. The sporadic and inherited forms as well as the
form acquired by infection, express three distinct,
major phenotypes: Creutzfeldt–Jakob disease (CJD),
fatal familial insomnia (FFI ) and Gerstmann–
Sträussler–Scheinker disease (GSS) [52].
A minority of cases of the inherited form cannot be
accommodated in any of these phenotypes and are
included in a heterogeneous group (Table 5). Two
critical histopathological features of the prion diseases
are the form and distribution of the deposits of PrPres.
The PrPres may form deposits like the so-called
punched out or kuru plaques, the multicentric plaques
commonly associated with GSS and the ‘florid’ plaques
of the new variant CJD. These plaques have the
Table 5. Classification of prion diseases
Form
Inherited
Phenotype
Creutzfeldt–Jakob disease (CJD)
Fatal familial insomnia (FFI )
Gerstmann–Sträussler–Scheinker
(GSS)
Heterogeneous
Sporadic
CJD
Sporadic form of FFI?
Acquired by an infectious Kuru
mechanism
Iatrogenic CJD (iCJD)
New variant of CJD (vCJD)?
Human brain amyloidoses
tentorial characteristics of the amyloid, they are associated with structural damage of the cerebral parenchyma and, therefore, they are detectable not only
following immunostaining but also with routine histological stains. Thus, they share many of the features
of the mature plaques of AD. The second type of
PrPres deposits are detectable only following immunostaining and not with routine histological stains. They
do not have the tentorial characteristics of the amyloid,
they may be present without obvious damage of the
parenchyma immediately adjacent to them and, therefore, they are reminiscent of the diffuse plaques of AD.
However, the parenchyma usually shows widespread
damage and, contrary to AD, these deposits are commonly symptomatic. Some of the biophysical events
resulting in the conversion of PrPc into PrPres are
relatively well known. The central event is a change of
the secondary structure which is predominantly ahelical in PrPc and becomes predominantly b-pleated
sheet in PrPres. These changes probably determine the
aggregability and resistance to proteases that are characteristic of PrPres. However, it is unclear how and
why PrP, presumably PrPres, forms amyloid deposits
only in some, and not in all, the phenotypes. Analysis
of protein composition has shown that PrP amyloid
contains primarily two internal peptides of ~11 and
~7 kDa spanning PrP residues 58–150 and 81–150,
respectively [53]. Moreover, in vitro studies have shown
that synthetic peptides encompassing PrP residues
106–126 and 127–147 which, therefore, are internal
fragments of the 11 and 7 kDa fragments readily form
amyloid fibrils [51]. These findings suggest that PrPc
or PrPres must undergo proteolytic cleavage to generate
amyloid.
Conclusions
Cerebral amyloidoses, although histopathologically
diverse, have, not surprisingly, similar mechanisms of
conversion of the amyloidogenic protein into amyloid
deposits. The pivotal event in all of the amyloidoses
appears to be a change in conformation which enhances
the amyloidogenicity of the protein involved in the
amyloid deposits. The conformational change is caused
by the presence of a mutation in the amyloidogenic or
amyloid precursor protein in the inherited amyloidoses,
is supposedly spontaneous in the sporadic forms, and
is transmitted through contamination in the forms of
prion diseases acquired by an infectious mechanism.
In AD, prion diseases and probably other amyloidoses, the deposition of true amyloid is preceded by
the presence of non-amyloid soluble aggregates which
may remain asymptomatic or are associated with the
disease.
In TTR amyloidosis, the entire protein participates
in the formation of the amyloid deposits; in prion
diseases, the entire protein participates in the nonamyloid soluble aggregate formation, but apparently
only internal fragments are involved in amyloid formation; in AD, an internal fragment, Ab, plays a central
39
role in the formation of both non-amyloid and amyloid
aggregates.
In DS, we have demonstrated for the first time that
the formation of amyloid and non-amyloid aggregates
of the AD type is in turn preceded for many years by
the abnormal presence of the amyloidogenic peptide
in water-soluble form. Whether this pathogenetic event
is also present in the other forms of AD and in other
amyloidoses remains to be determined.
The chapter of the brain amyloidoses is undergoing
profound changes, as an amyloidogenesis-like process
seems to play a critical role in the pathogenesis of
several neurodegenerative diseases.
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