Download Prion diseases

Genetic aspects of Alzheimer disease
Karolina Pesz, Błażej Misiak, Maria M. Sasiadek
Department of Genetics
Wroclaw Medical University, Poland
Alois Alzheimer
(born: 1864, Marktbreit, died: 1915, Wrocław)
Alzheimer disease:
early and late onset
Alzheimer disease – etiology
Alzheimer disease
molecular pathogenesis
Alzheimer disease
molecular pathogenesis
Alzheimer disease - genetics
•
•
•
•
•
•
APP
PS-1
PS-2
ApoE
L2M
LRP1
•
•
•
•
•
•
21.q21 (EOAD)
14.q24 (EOAD)
1p4.1 (EOAD)
19q13 (LOAD)
12q13 (LOAD)
12q13 (LOAD)
Alzheimer disease
Early onset Alzheimer disease
This is a rare form of Alzheimer's disease in
which people are diagnosed with the disease
before age 65. Less than 10% of all Alzheimer's
disease patients have this type. Because they
experience premature aging, people with Down
syndrome are particularly at risk for a form of
early onset Alzheimer's disease. Adults with
Down syndrome are often in their mid- to late
40s or early 50s when symptoms first appear.
Early onset Alzheimer disease –
APP (21q21)
Early onset Alzheimer disease –
presenilin 1 and 2 (14q24; 1p41)
Ju-Hyun Lee et al. Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by AlzheimerRelated PS1 Mutations Cell, 141, 1146-1158, 2010
Highlights:
► Presenilin-1 (PS1) is essential for lysosomal acidification and protein
degradation
► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1
► PS1 mutations impair lysosomal acidification and protein turnover by
autophagy
► Neurons in PS1-deficient mice have lysosomal acidification deficits
Early onset Alzheimer disease –
presenilin 1 and 2 (14q24; 1p41)
Tau protein (17q21)
Axonal transport relies on microtubules as tracks,
stabilized by the ties of tau protein.
Six isoforms of Tau protein, generated through alternative splicing
MUTATIONS (exons 2, 3 i 10)
• tau with altered binding to microtubules,
• tau agreggations in form of paired helical filaments
• rapid formation of beta structures
AD: neurofibllary tangles are made up of paired helical filaments
of 6 hyperphosphorylated isoforms of tau protein.
Tau protein:
Model showing a possible link between axonal transport, microtubules and
tau in Alzheimer's disease. Phosphorylation (P) at crucial sites detaches tau
from microtubules, leading to the breakdown of microtubules and the
accumulation of tau aggregated into paired helical filaments (PHFs).
Tau protein:
The 'assembly domain' comprises the C-terminal half; it binds to microtubules
and stabilizes them, whereas the N-terminal 'projection domain' protrudes from
the microtubule surface. (www.mpasmb-hamburg.mpg.de/.../taubilder.htm)
Late onset Alzheimer
diseasehttp://www.webmd.com/alzheimers/guide/alzheimers-types
Apolipoprotein E
Apolipoprotein E
Nature Reviews Neuroscience 1, 51-58 (2000) J. Herz & U. Beffert
The APOE4 conundrum
Osherovich L., SciBX 2(24); 2009
Two studies suggest different theories of how APOE4 (E4) works in Alzheimer's disease
(AD), and thus they offer different ways of blocking its action. Normal APOE carries
lipids between various cells in the brain.
In E4 carriers, the smaller E4 particles compete with full-sized APOE variants [1a],
leading to insufficient lipid delivery and higher levels of β-amyloid (Aβ) aggregation.
That, in turn, leads to neuronal degeneration [2] and, eventually, to AD [3].
An alternative theory proposed by Mahley et al. postulates that E4 originating from
within neurons is proteolytically cleaved into fragments that interfere with
mitochondrial activity [1b], leading to neurodegeneration and AD. Other APOE
variants are not subject to this proteolytic processing and are thus not toxic.
LDL receptor-related protein
Gene dysregulation versus
microRNA
• Maes et al. (2007) - systemic gene deregulation:
Expression profiling study: significant changes in gene expression
in sporadic AD individuals as compared to aged-matched normal
elderly controls. Different groups of genes showed a significant
decrease in expression in AD subjects; mainly genes responsible
for cytoskeletal maintenance, cellular trafficking and stress
response, redox homeostasis, transcription and DNA repair.
Moreover some of the deregulated genes are believed to play a
role in -amyloid aggregation and protein tau phosphorylation.
• Huppi et al. (2007):
MicroRNAs may regulate as may as one third to one half of all
protein encoding genes.
• Wang et al. (2008):
In early AD the expression of microRNA miR-107 decreases.
Gene dysregulation versus
microRNA
Summarizing:
The presentation was prepared, using
pictures available on following pages:
•
•
•
•
•
http://www.nia.nih.gov/Alzheimers/Publications/geneticsfs.htmhttp://ww
w.webmd.com/alzheimers/guide/alzheimersgenetichttp://www.genetichealth.com/alz_genetics_of_alzheimers_disease
.shtmlhttp://www.accessdna.com/condition/Alzheimer_s_Disease/31http:/
/medinfo.ufl.edu:8050/year1/humbehav/readingmat/goldalzheimers_genes.pdfhttp://ki.se/ki/jsp/polopoly.jsp?d=25844&a=8774&l=
en&newsdep=25844•
http://www.cnsforum.com/imagebank/item/PRESEN_MUT_ALZ/default.as
px
diseasehttp://www.webmd.com/alzheimers/guide/alzheimers-types
http://content.answcdn.com/main/content/img/oxford/Oxford_Mind/019
8162246.alzheimers-disease.1.jpg
www.mpasmb-hamburg.mpg.de/.../taubilder.htm