Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques
Open accessAbstract
Genetic analysis of familial forms of Alzheimer's disease (AD) causally links the proteolytic processing of the amyloid precursor protein (APP) and AD. However, the specific type of amyloid and mechanisms of amyloid pathogenesis remain unclear. We conducted a detailed analysis of intracellular amyloid with an aggregation specific conformation dependent monoclonal antibody, M78, raised against fibrillar Aß42. M78 immunoreactivity colocalizes with Aß and the carboxyl terminus of APP (APP-CTF) immunoreactivities in perinuclear compartments at intermediate times in 10month 3XTg-AD mice, indicating that this represents misfolded and aggregated protein rather than normally folded APP. At 12months, M78 immunoreactivity also accumulates in the nucleus. Neuritic plaques at 12months display the same spatial organization of centrally colocalized M78, diffuse chromatin and neuronal nuclear NeuN staining surrounded by peripheral M78 and APP-CTF immunoreactivity as observed in neurons, indicating that neuritic plaques arise from degenerating neurons with intracellular amyloid immunoreactivity. The same staining pattern was observed in neuritic plaques in human AD brains, showing elevated intracellular M78 immunoreactivity at intermediate stages of amyloid pathology (Braak A and B) compared to no amyloid pathology and late stage amyloid pathology (Braak 0 and C, respectively). These results indicate that intraneuronal protein aggregation and amyloid accumulation is an early event in AD and that neuritic plaques are initiated by the degeneration and death of neurons by a mechanism that may be related to the formation of extracellular traps by neutrophils.
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Plaque formation depends on neuronal amyloid beta.
“This aligns with work from multiple laboratories showing that plaque formation depends on neuronal Aβ [45–48]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [46]
The Discussion supports a neuronal origin for neuritic plaques: it says the observed staining patterns suggest plaques arise from degenerating neurons containing intracellular amyloid-related material. But it describes the material as Aβ, APP, or APP-CTFs and does not establish that plaque formation depends specifically on neuronal Aβ. (LLM, conf=0.85)
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References 42 · Cited by 120
- Authors
- Pensalfini, A., Albay, R., Rasool, S., Wu, J. W., Hatami, A., Arai, H., Margol, L., Milton, S., Poon, W. W., Corrada, M. M., Kawas, C. H., & Glabe, C. G.
- Affiliations
- University of California, Irvine (US)
- King Abdulaziz University (SA)
- Corresponding author
- Pensalfini, Anna
- Glabe, Charles G.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 71
- Pages
- 53-61
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4179983
- OpenAlex
- W2005765994
- Cited by
- 120
- References
- 42
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 23 · 2023: 10 · 2022: 13 · 2021: 16 · 2020: 7 · 2019: 10 · 2018: 9 · 2017: 7 · 2016: 8 · 2015: 3
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R01AG21055)
- National Cancer Institute
- Cure Alzheimer's Fund
- National Institutes of Health (P30CA062203, AG 033069, AG00538)
- Topics
- Health Sciences › Medicine › Physiology › 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
- neuritic plaques, Alzheimer's disease, amyloid precursor protein, amyloid-beta 42, 3xTg-AD mice, neurodegeneration, Braak stages, neutrophil extracellular traps, protein aggregation
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cell Nucleolus, Cytoplasm, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Neurons, Peptide Fragments, Phosphopyruvate Hydratase, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, alpha-Synuclein, Presenilin-1, Plaque, Amyloid
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