Down syndrome and Alzheimer's disease: common molecular traits beyond the amyloid precursor protein

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Abstract

Alzheimer’s disease (AD) is the most prevalent type of dementia. Down syndrome (DS) is the leading genetic risk factor for Early-Onset AD, prematurely presenting the classic pathological features of the brain with AD. Augmented gene dosage, including the APP gene, could partially cause this predisposition. Recent works have revealed that alterations in chromosome location due to the extra Chromosome 21, as well as epigenetic modifications, could promote changes in gene expression other than those from Chromosome 21. As a result, similar pathological features and cellular dysfunctions in DS and AD, including impaired autophagy, lysosomal activity, and mitochondrial dysfunction, could be controlled beyond APP overexpression. In this review, we highlight some recent data regarding the origin of the shared features between DS and AD and explore the mechanisms concerning cognitive deficiencies in DS associated with dementia, which could shed some light into the search for new therapeutic targets for AD treatment.

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Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

E H Corder, A M Saunders, W J Strittmatter … (1993)

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

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Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

A Saunders, W J Strittmatter, D Schmechel … (1993)

Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

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Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

D Scheuner, C Eckman, M. Jensen … (1996)

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

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Author and article information

Journal

Journal ID (nlm-ta): Aging (Albany NY)

Journal ID (iso-abbrev): Aging (Albany NY)

Journal ID (publisher-id): Aging

Title: Aging (Albany NY)

Publisher: Impact Journals

ISSN (Electronic): 1945-4589

Publication date Collection: 15 January 2020

Publication date (Electronic): 09 January 2020

Volume: 12

Issue: 1

Pages: 1011-1033

Affiliations

[1 ]Laboratory of Neuroprotection and Autophagy, Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile

[2 ]Departamento de Bioquímica y Biología Molecular and Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile

[3 ]Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA

[4 ]CIBQA, Universidad Bernardo O’Higgins, Santiago, Chile

[5 ]Centro de Modelamiento Molecular, Biofísica y Bioinformática (CM2B2), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile

[6 ]Center for Exercise, Metabolism, and Cancer Studies (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, Chile

[7 ]Autophagy Research Center, Universidad de Chile, Santiago, Chile

[8 ]Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago, Chile

Author notes

Correspondence to: Valentina Parra; email: vparra@ciq.uchile.cl

Correspondence to: Melissa Nassif; email: melissa.calegaro@umayor.cl

Article

Publisher ID: 102677 Publisher ID: 102677

DOI: 10.18632/aging.102677

PMC ID: 6977673

PubMed ID: 31918411

SO-VID: 28e9aa53-612c-468a-a396-dcaf4fa01703

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Down syndrome and Alzheimer's disease: common molecular traits beyond the amyloid precursor protein

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Most cited references 75

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

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