Cited by 332Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

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Baranello, Robert, Bharani, Krishna, Padmaraju, Vasudevaraju, Chopra, Nipun, Lahiri, Debomoy, Greig, Nigel, Pappolla, Miguel, Sambamurti, Kumar·2015·Current Alzheimer Research

DOI 10.2174/1567205012666141218140953PMC PMC4820400

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Abstract

Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

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“Additionally, ACE inhibits A toxicity in cultured PC12 cells, blocks the aggregation of synthetic A , and cleaves A between the Asp 7 -Ser 8 residues [160, 161].”
Background
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“There is also evidence that ApoE facilitates aggregation and polymerization of A into amyloid fibrils, a process that is less efficiently carried out by the ApoE- 4 allele [59-63].”
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Research works printed but not linked: 1

[23]Sambamurti K Greig NH Utsuki T Barnwell EL Sharma E Mazell C Targets for AD treatment: conflicting messages from gamma-secretase inhibitors J Neurochem 117 3 359 74 2011 21320126 PMC3076515

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See all 332

Authors: Baranello, R., Bharani, K., Padmaraju, V., Chopra, N., Lahiri, D., Greig, N., Pappolla, M., & Sambamurti, K.
Affiliations: Medical University of South Carolina (US)
Indiana University – Purdue University Indianapolis (US)
Indiana University Bloomington (US)
National Institutes of Health (US)
The University of Texas Medical Branch at Galveston (US)
ORCID: Bharani, Krishna
Padmaraju, Vasudevaraju
Chopra, Nipun
Lahiri, Debomoy
Greig, Nigel
Pappolla, Miguel
Sambamurti, Kumar
Venue: Current Alzheimer Research
Publisher: Bentham Science Publishers Ltd.
Published: 2015-01-03
Volume: 12
Issue: 1
Pages: 32-46
ISSN: 1567-2050 (ISSN-L)
DOI: 10.2174/1567205012666141218140953
PMC: PMC4820400
OpenAlex: W2136334732
Cited by: 331
References: 201
Citations by year: 2026: 9 · 2025: 26 · 2024: 14 · 2023: 30 · 2022: 34 · 2021: 44 · 2020: 45 · 2019: 45 · 2018: 31 · 2017: 22 · 2016: 20 · 2015: 10
FWCI: 20.39
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Current Alzheimer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
IUScholarWorks (Indiana University) (submittedVersion)
Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders: National Institutes of Health (5r21ag042804-02)
National Institute on Aging (R21-AG042804, AG046200, R01AG022103, R21AG046200, AG042804)
National Institute of General Medical Sciences (T32 GM08716-13, T32GM008716)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: amyloid-beta, Alzheimer's disease, amyloid-beta clearance, amyloid beta degradation, amyloid plaques, familial Alzheimer's disease, APP mutations, presenilin, gamma-secretase, BACE1, insulin-degrading enzyme, neprilysin, matrix metalloproteinases, APOE ε4, gamma-secretase inhibitors
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Humans, Models, Biological, Mutation, Signal Transduction, Amyloid beta-Peptides, Presenilin-1, Presenilin-2, Amyloid Precursor Protein Secretases, Plaque, Amyloid

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Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

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