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Content archived on 2024-06-18

Study of the aging-related changes of the gamma-secretase complex and evaluation to what extent those contribute to amyloid accumulation in sporadic Alzheimer’s disease

Objective

Alzheimer’s disease (AD) is the most common form of dementia. The main hallmark of AD is presence of the extraneuronal senile plaques composed of amyloid beta-peptide (Aβ). Aβ is produced when a transmembrane glycoprotein called Amyloid Precursor Protein (APP) is consecutively cleaved by two proteases: the γ-secretase and the β-secretase. γ-Secretase can render distinct length isoforms of Aβ, with Aβ40 and Aβ42 most studied in the context of AD pathology. Aging is the single most important risk factor for sporadic AD. The molecular basis for this remains unclear. In the rare genetic forms of AD, i.e. familial AD (FAD) mutations in the genes involved in the production of Aβ are causative, strongly suggesting that abnormal Aβ generation can cause the disease. For the sporadic disease it is mostly proposed that lack of Aβ clearance is involved in the Abeta accumulation, but direct proof for this hypothesis is lacking, and the possibility that changes in Abeta production are playing a role becomes an interesting possibility. It has been shown that clinical mutations in the catalytic subunit of γ-secretase act by loss of function of the protease, which makes it conceivable that loss of function effects in aging might have similar effects on γ-secretase in the aged brain. This assumption finds support in interesting observations that Aβ42 becomes elevated in the brain of sporadic AD patients and in rodent models of the disease at advanced age. Moreover, some recent evidences in rodents corroborate this hypothesis even further as an age-dependent shift of γ-secretase activity towards a higher Aβ42 production was observed. The main goals of our project are accordingly: (1) evaluation of changes in γ-secretase activity in the aging brain by evaluating the effects on Aβ production (2) to elucidate the age-associated molecular events responsible for these changes. The outcome of these studies can shed light on the origin of this devastating disease in the elderly.

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Topic(s)

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Call for proposal

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FP7-PEOPLE-2009-IEF
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Funding Scheme

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MC-IEF - Intra-European Fellowships (IEF)

Coordinator

VIB VZW
EU contribution
€ 160 100,00
Address
SUZANNE TASSIERSTRAAT 1
9052 ZWIJNAARDE - GENT
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

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