Trafficking and Proteolytic Processing of APP
Open accessAbstract
Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.
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The observation reinforces the likely involvement of microglial endocytosis in Alzheimer's disease, a mechanism that is also strongly involved in APP metabolism.
“this observation reinforces the likely involvement of microglial endocytosis in AD, a mechanism that is also strongly involved in APP metabolism16”
From New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) · cites this paper as [16]
Quantum dots coated with PEG have been formulated into stable nanocomplexes capable of crossing the blood-brain barrier and effectively suppressed BACE1 gene expression in human neuroblastoma cells.
“For instance, QDs coated with a polyethylene glycol (PEG) layer have been formulated into stable nanocomplexes capable of crossing the BBB. These complexes effectively suppressed BACE1 gene expression in human neuroblastoma cells, demonstrating their potential in AD therapy [112].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [112]
The section on familial Alzheimer disease-associated APP mutations describes BACE1 as a therapeutic target, but does not discuss quantum dots, PEG-coated nanocomplexes, blood–brain barrier crossing, or suppressed BACE1 gene expression in human neuroblastoma cells. Searches for those terms and for nanoparticle-mediated BACE1 suppression found no passage addressing the cited claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredADAM10 is the most important α-secretase in the brain, is a component of the non-amyloidogenic pathway of APP metabolism, and sheds TREM2.
“ADAM10, the most important α-secretase in the brain, is a component of the non-amyloidogenic pathway of APP metabolism67 and sheds TREM2 (ref. 68)”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [67]
Aβ is produced by sequential cleavage of APP by β-secretase and γ-secretase.
“Aβ is produced by sequential cleavage of β-amyloid precursor protein (APP) by β-secretase and γ-secretase”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Haass et al., 2012
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References 200 · Cited by 1,075
- Authors
- Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- University of Chicago (US)
- Corresponding author
- Haass, C.
- Sisodia, S.
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-02-07
- Volume
- 2
- Issue
- 5
- Pages
- a006270-a006270
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC3331683
- OpenAlex
- W2167693778
- Cited by
- 1,075
- References
- 200
- Citations by year
- 2026: 45 · 2025: 52 · 2024: 82 · 2023: 80 · 2022: 97 · 2021: 92 · 2020: 96 · 2019: 81 · 2018: 76 · 2017: 88 · 2016: 80 · 2015: 81 · 2014: 67 · 2013: 43 · 2012: 11
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
- Funders
- National Institute on Aging (R01AG019070)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid precursor protein, APP trafficking, secretases, beta-secretase, gamma-secretase, alpha-secretase, amyloid-beta, Alzheimer's disease, secretory pathway, neuronal activity, APP processing
- MeSH terms
- Alzheimer Disease, Humans, Mutation, Neurons, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Protein Transport, Metalloproteases, Amyloid Precursor Protein Secretases, Proteolysis
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