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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2019

Open Access 01-08-2019 | Alzheimer's Disease | Review

The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

Authors: Pierre Dourlen, Devrim Kilinc, Nicolas Malmanche, Julien Chapuis, Jean-Charles Lambert

Published in: Acta Neuropathologica | Issue 2/2019

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Abstract

A strong genetic predisposition (60–80% of attributable risk) is present in Alzheimer’s disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approaches and emerging neurobiological information, we propose an over-arching model in which the focal adhesion pathway and the related cell signalling are key elements in AD pathogenesis. The core of the focal adhesion pathway links the physiological functions of amyloid precursor protein and Tau with the pathophysiological processes they are involved in. This model includes several entry points, fitting with the different origins for the disease, and supports the notion that dysregulation of synaptic plasticity is a central node in AD. Notably, our interpretation of the latest data from genome wide association studies complements other hypotheses already developed in the AD field, i.e., amyloid cascade, cellular phase or propagation hypotheses. Genetically driven synaptic failure hypothesis will need to be further tested experimentally within the general AD framework.
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Literature
1.
2.
3.
4.
5.
Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J et al (1999) Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 96:15233–15238CrossRefPubMedPubMedCentral
6.
7.
Bamburg JR, Bernstein BW (2016) Actin dynamics and cofilin–actin rods in alzheimer disease. Cytoskeleton 73:477–497CrossRefPubMed
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Daudin R, Marechal D, Wang Q, Abe Y, Bourg N, Sartori M et al (2018) BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal cortex-dentate gyrus pathway and related hippocampal multi-scale impairments. bioRxiv. https://​doi.​org/​10.​1101/​437228 CrossRef
23.
24.
DeMattos RB, Cirrito JR, Parsadanian M, May PC, O’Dell MA, Taylor JW et al (2004) ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41:193–202CrossRefPubMed
25.
Dourlen P (2017) Identification of Tau toxicity modifiers in the Drosophila eye. Methods Mol Biol 1523:375–389CrossRefPubMed
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
Grace EA, Busciglio J (2003) Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy. J Neurosci 23:493–502CrossRefPubMedPubMedCentral
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
Huang Y, Lu W, Ali DW, Pelkey KA, Pitcher GM, Lu YM et al (2001) CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron 29:485–496CrossRefPubMed
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
Kirsch KH, Georgescu MM, Ishimaru S, Hanafusa H (1999) CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc Natl Acad Sci USA 96:6211–6216CrossRefPubMedPubMedCentral
75.
76.
77.
78.
Lamartinière Y, Boucau M-C, Dehouck L, Krohn M, Pahnke J, Candela P et al (2018) ABCA7 downregulation modifies cellular cholesterol homeostasis and decreases amyloid-β peptide efflux in an in vitro model of the blood–brain barrier. J Alzheimers Dis 64:1195–1211. https://​doi.​org/​10.​3233/​jad-170883 CrossRefPubMed
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
Mukherjee S, Russell JC, Carr DT, Burgess JD, Allen M, Serie DJ et al (2017) Systems biology approach to late-onset Alzheimer’s disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments. Alzheimer’s Dement. https://​doi.​org/​10.​1016/​j.​jalz.​2017.​01.​016 CrossRef
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
Sabo SL, Ikin AF, Buxbaum JD, Greengard P (2001) The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol 153:1403–1414CrossRefPubMedPubMedCentral
109.
110.
111.
112.
113.
114.
115.
Selkoe DJ, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB et al (1996) The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann N Y Acad Sci 777:57–64CrossRefPubMed
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S et al (2002) Rapid tyrosine phosphorylation of neuronal proteins including Tau and focal adhesion kinase in response to amyloid-beta peptide exposure: involvement of Src family protein kinases. J Neurosci 22:10–20CrossRefPubMedPubMedCentral
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
Metadata
Title
The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?
Authors
Pierre Dourlen
Devrim Kilinc
Nicolas Malmanche
Julien Chapuis
Jean-Charles Lambert
Publication date
01-08-2019
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 2/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-019-02004-0

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