Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis
Open accessAbstract
One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid β peptide (Aβ), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into Aβ, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and Aβ generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and Aβ generation. Conversely, PICALM overexpression increased APP internalization and Aβ production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble Aβ levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased Aβ levels and amyloid plaque load. These…
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Reducing or overexpressing PICALM levels in hippocampal neurons of APP Swe; PSEN1 L166P mice with AAV8-mediated delivery of PICALM shRNA or cDNA indicated that PICALM might regulate Aβ production.
“However, reducing or overexpressing PICALM levels in hippocampal neurons of APP Swe ; PSEN1 L166P mice with AAV8-mediated delivery of PICALM shRNA or cDNA, respectively, indicated that PICALM might regulate A 𝛃 production (658).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [658]
PICALM underexpression decreases levels of APP catabolites and reduces APP internalisation and Aβ generation.
“PICALM underexpression decreases the levels of several APP catabolites, such as intracellular β-C-terminal fragment (β-CTF) and secreted sAPPβ, which has been attributed to its role in clathrin-mediated endocytosis [134].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [148]
PICALM knockdown and overexpression respectively decreased and increased amyloid plaque loads in the hippocampi of 6-month-old APP/PS1 mice.
“As opposed to BIN1 and CD2AP, PICALM knockdown and overexpression, respectively, decreased and increased amyloid plaque loads in the hippocampi of 6-month-old APP/PS1 mice [148].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [148]
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- Authors
- Xiao, Q., Gil, S.-C., Yan, P., Wang, Y., Han, S., Gonzales, E., Perez, R., Cirrito, J. R., & Lee, J.-M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Lee, Jin-Moo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 287
- Issue
- 25
- Pages
- 21279-21289
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3375549
- OpenAlex
- W2046234674
- Semantic Scholar
- 69363ebb87e63fac1c9442658d5a2bff98dad5ce
- Cited by
- 166
- References
- 48
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 12 · 2019: 19 · 2018: 16 · 2017: 16 · 2016: 17 · 2015: 14 · 2014: 18 · 2013: 16 · 2012: 2
- FWCI
- 9.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute on Aging (K01 AG029524)
- National Institute of Neurological Disorders and Stroke (P01 NS32636, R01 NS067905, R01 NS67905, P01 NS032636)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- PICALM, amyloid precursor protein, amyloid-beta, Alzheimer's disease, amyloid plaques, clathrin-mediated endocytosis, APP processing, APP/PS1 mice, hippocampus, shRNA knockdown, single nucleotide polymorphisms
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Clathrin, Hippocampus, Humans, Transduction, Genetic, Amyloid beta-Protein Precursor, Monomeric Clathrin Assembly Proteins, Cell Line, Tumor, Mice, Gene Knockdown Techniques, Plaque, Amyloid
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