Year: 2008
Type: article
Abstract: Alzheimer's disease (AD) is a progressive dementia with characteristic brain lesions known as senile plaques and neurofibrillary tangles (NFTs).Amyloid plaques contain the 38-42 residue amyloid-β protein (Aβ) and NFTs consist of the microtubule-associated protein, tau [18].Aβ is synthesized as a larger precursor protein -AβPP -and is generated by proteolytic processing by βand γ-secretases [15].For a number of years, the field debated whether senile plaques or NFTs are causes of the disease or simply markers or tombstones that define AD.A major series of discoveries in the early 1990s started to place amyloid at the center of the disease pathology by finding mutations framing the Aβ sequence on AβPP linked to rare familial AD (FAD).In addition, the field developed methods for analysis of small peptides and determined that the yield of either total Aβ or the longer Aβ42 fragment was increased in cells expressing FAD mutant AβPP.Subsequently, a larger number of FAD mutations linked to a subunit of γ-secretase termed presenilins (PS) 1 and 2 were identified.Most of these mutations also increased Aβ42 levels.Since the longer Aβ42 form readily aggregates to form amyloid deposits, the theory that amyloid plaques cause AD became well supported [7].The finding that Aβ aggregates were neurotoxic in culture further supported the amyloid hypothesis.However, as the field matured, it became clear that there were a number of weaknesses in the one-dimensional
Source: Journal of Alzheimer s Disease
Institution: Medical University of South Carolina
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: National Institute on Aging
OpenAlex ID: W2119326508