Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer's disease

Kumar Sambamurti, Nigel H. Greig, Debomoy Lahiri

Research output: Contribution to journalArticle

189 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (Aβ) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as "secretases" participate in APP processing. An enzymatic activity, β-secretase, cleaves APP on the amino side of Aβ producing a large secreted derivative, sAPPβ, and an Aβ-bearing membrane-associated C-terminal derivative, CTFβ, which is subsequently cleaved by the second activity, γ-secretase, to release Aβ. Alternatively, a third activity, α-secretase, cleaves APP within Aβ to the secreted derivative sAPPα and membrane-associated CTFα. The predominant secreted APP derivative is sAPPα in most cell-types. Most of the secreted Aβ is 40 residues long (Aβ40) although a small percentage is 42 residues in length (Aβ42). However, the longer Aβ42 aggregates more readily and was therefore considered to be the pathologically important form. Advances in our understanding of APP processing, trafficking, and turnover will pave the way for better drug discovery for the eventual treatment of AD. In addition, APP gene regulation and its interaction with other proteins may provide useful drug targets for AD. The emerging knowledge related to the normal function of APP will help in determining whether or not the AD associated changes in APP metabolism affect its function. The present review summarizes our current understanding of APP metabolism and function and their relationship to other proteins involved in AD.

Original languageEnglish
Pages (from-to)1-31
Number of pages31
JournalNeuroMolecular Medicine
Volume1
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Protein Precursors
Amyloid beta-Peptides
Cell Biology
Molecular Biology
Alzheimer Disease
Amyloid Precursor Protein Secretases
Presenilin-2
Presenilin-1
Genetically Modified Animals
Proteins
Microtubule-Associated Proteins
Membranes
Amyloid Plaques
Apolipoproteins E
Protein Transport
Drug Discovery
Peptides
Mutation

Keywords

  • Abeta
  • Amyloid precursor protein
  • BACE
  • Presenilin
  • Secretase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer's disease. / Sambamurti, Kumar; Greig, Nigel H.; Lahiri, Debomoy.

In: NeuroMolecular Medicine, Vol. 1, No. 1, 2002, p. 1-31.

Research output: Contribution to journalArticle

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