Amyloid Precursor Protein Processing and Alzheimer’s Disease

By Richard O'Brien, Philip C. Wong. Annual Review of Neuroscience, 2011

1,952 citations recorded by the source corpus.

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.

Subfields: Computational Theory and Mathematics, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/4d0029ad10c313d236922be0396c6769b9ae212b

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In Pharmacology

1. Dennis W. Dickson
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Citations in the corpus

• Caspase functions in cell death and disease. (2013, background): “Caspase-mediated cleavage of b-amyloid precursor protein (APP) has been reported (Rohn et al. 2001), as has caspase activation by amyloid-bpeptide (O’Brien and Wong 2011).”
• The neuropathological diagnosis of Alzheimer’s disease (2019, background): “There are many reviews describing the generation of Aβ peptides [32], and these pathways remain viable therapeutic targets.”
• Inflammation as a central mechanism in Alzheimer's disease (2018, background): “The function of APP is unknown but is believed to have a role in cell health and growth [5].”
• Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics (2019, background): “Young onset of the disease is attributed to predisposition to PS1 genetic mutation, which is a rare but potent cause.(7) Other neurodegenerative Correspondence: Madhavan Nair Department of Immunology and NanoMedicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Flori”
• A proteomic atlas of senescence-associated secretomes for aging biomarker development (2019, background): “neurodegeneration proteins were amyloid precursor protein (APP) and cystatin 3 (CST3), related to Alzheimer’s pathogenesis and risk (Kaur and Levy, 2012; O’Brien and Wong, 2011), as well as Parkinsonism-associated deglycase (PARK7 or DJ1) (Bonifati et al.”
• Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies (2024, background): “78,111,112 115 However, FAD mutations are not necessarily linked to an increase in A β 42 levels or an elevation of A β 42 /A β 40 ratio.”
• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “APP homodimers may function as cellsurface G-protein coupled receptors which can bind Aβ, and mediate neuronal signaling and neurotransmitter release through the activation of calcium channels [17, 19].”