The Pathogenesis of Senile Plaques
Abstract
Senile plaques (SP) are complicated lesions composed of diverse amyloid peptides and associated molecules, degenerating neuronal processes,a nd reactive glia. Evidence suggests that diffuse, neurocentric amyloid deposits evolve over time with formation of discrete niduses that eventually become neuritic SP. The evidence for differential amyloid precursor protein metabolism that may favor deposition of A beta 17-42 in this early, possibly aging-related lesion is discussed. This latter molecule, also known as P3, may represent a benign form of amyloid, since it lacks domains associated with activation and recruitment of glia to SP. Subsequent to deposition of A beta 1-42 and then growth of the amyloid with precipitation of soluble A beta 1-40, in an Alzheimer disease-specific process, SP increasingly become associated with activated microglia and reactive astrocytes. In response to interaction with amyloid peptides and possibly glycated proteins, microglia and astrocytes produce a number of molecules that may be locally toxic to neuronal processes in the vicinity of SP, including cytokines, reactive oxygen and nitrogen intermediates, and proteases. They also produce factors that lead to their reciprocal activation and growth, which potentiate a local inflammatory cascade. Paired helical filament- (PHF) type neurites appear to be associated with SP only in so far as neurofibrillary degeneration has progressed to affect neurons in those regions where the plaque forms. Thus, PHF-type neurites are readily apparent in SP in the amygdala at an early stage, while they are late in primary cortices and never detected in cerebellar plaques; where only dystrophic neurites are detected. If the various stages of SP pathogenesis can be further clarified, it may be possible to develop rational approaches to therapy directed at site-, cell type-, and stage-specific interventions. Although controlling the local inflammatory microenvironment of SP may hold promise for slowing lesion pathogenesis, it still remains a fundamental challenge to determine the mechanism of neurodegeneration that results in widespread neurofibrillary degeneration and eventual synaptic and neuronal loss, which is considered to be the proximate cause of the clinical dementia syndrome.
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A subset of dense core plaques have neuritic elements, and these cored neuritic plaques can be associated with tau-positive or dystrophic neurites.
“More importantly, a subset of dense core plaques have neuritic elements as shown in Fig. 2c, d, and these cored neuritic plaques (NPs) can be associated with tau-positive or dystrophic neurites”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [33]
Diffuse plaques often lack neuritic components, though diffuse neuritic plaques can be observed in advanced Alzheimer's disease.
“In contrast, diffuse plaques often lack neuritic components, though diffuse neuritic plaques can be observed in advanced AD [33].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [33]
The two types of amyloid plaques most commonly observed in Alzheimer's disease are diffuse plaques and dense core plaques.
“the two types of amyloid plaques most commonly observed in AD are diffuse plaques and dense core plaques [29, 33]”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [33]
Immunohistochemical stains for neuritic processes identify specific, partially overlapping subtypes of dystrophic neurites that may differ in disease relevance.
“immunohistochemical stains for neuritic processes, such as amyloid precursor protein, ubiquitin, neurofilament or phospho-tau, will identify specific, and partially overlapping, subtypes of dystrophic neurites that may differ in disease relevance [21].”
From National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach (2012) · cites this paper as [21]
TNF-α co-localizes with plaques in post-mortem analysis of AD brains.
“Investigation into TNF-α signaling in AD first began when it was found to co-localize with plaques in post-mortem analysis of AD brains [144].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [144]
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“2c, d, and these cored neuritic plaques (NPs) can be associated with tau-positive or dystrophic neurites, the latter demonstrated with a variety of markers including synaptic and APP immunohistochemistry [33].”
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Buerger, K., Ewers, M., Pirttila, T., Zinkowski, R., Alafuzoff, I., Teipel, S. J., DeBernardis, J., Kerkman, D., McCulloch, C., Soininen, H., et al. (2006) · Brain · doi:10.1093/brain/awl269 · Cited by 586 · see citing works
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Mackic, J. B., Stins, M., McComb, J. G., Calero, M., Ghiso, J., Kim, K. S., Yan, S. D., Stern, D., Schmidt, A. M., Frangione, B., et al. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2029 · Cited by 242 · see citing works
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Niwa, K., Porter, V. A., Kazama, K., Cornfield, D., Carlson, G. A., & Iadecola, C. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.6.h2417 · Cited by 202 · see citing works
Yates, S. L., Burgess, L. H., Kocsis‐Angle, J., Antal, J. M., Dority, M. D., Embury, P. B., Piotrkowski, A. M., & Brunden, K. R. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0741017.x · Cited by 202 · see citing works
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Kumar-Singh, S. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.18.2589 · Cited by 158 · see citing works
Martel, C. L., Mackic, J. B., Matsubara, E., Governale, S., Miguel, C., Miao, W., McComb, J. G., Frangione, B., Ghiso, J., & Zlokovic, B. V. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69051995.x · Cited by 149 · see citing works
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Thal, D. R., Schultz, C., Dehghani, F., Yamaguchi, H., Braak, H., & Braak, E. (2000) · Acta Neuropathologica · doi:10.1007/s004010000242 · Cited by 136 · see citing works
Thal, D. R., Griffin, W. S. T., & Braak, H. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00411.x · Cited by 134 · see citing works
Veerhuis, R., Van Breemen, M. J., Hoozemans, J. J., Morbin, M., Ouladhadj, J., Tagliavini, F., & Eikelenboom, P. (2003) · Acta Neuropathologica · doi:10.1007/s00401-002-0624-7 · Cited by 123 · see citing works
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Chakrabarty, P., Herring, A., Ceballos-Diaz, C., Das, P., & Golde, T. E. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-16 · Cited by 117 · see citing works
Thal, D. R., Attems, J., & Ewers, M. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141461 · Cited by 100 · see citing works
Montgomery, S. L., Mastrangelo, M. A., Habib, D., Narrow, W. C., Knowlden, S. A., Wright, T. W., & Bowers, W. J. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.07.001 · Cited by 96 · see citing works
Sani, S., Traul, D., Klink, A., Niaraki, N., Gonzalo-Ruiz, A., Wu, C.-K., & Geula, C. (2003) · Acta Neuropathologica · doi:10.1007/s00401-002-0626-5 · Cited by 83 · see citing works
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Cornejo, F., Vruwink, M., Metz, C., Muñoz, P., Salgado, N., Poblete, J., Andrés, M. E., Eugenín, J., & von Bernhardi, R. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2017.12.007 · Cited by 59 · see citing works
Delatour, B., Blanchard, V, Pradier, L., & Duyckaerts, C. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.01.008 · Cited by 60 · see citing works
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Capetillo-Zarate, E., Staufenbiel, M., Abramowski, D., Haass, C., Escher, A., Stadelmann, C., Yamaguchi, H., Wiestler, O. D., & Thal, D. R. (2006) · Brain · doi:10.1093/brain/awl176 · Cited by 45 · see citing works
Albrecht, D. S., Sagare, A., Pachicano, M., Sweeney, M. D., Toga, A., Zlokovic, B., Chui, H., Joe, E., Schneider, L., Morris, J. C., et al. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.01.010 · Cited by 37 · see citing works
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Kim, E.-J., Vatsavayai, S., & Seeley, W. W. (2016) · The Behavioral Neurology of Dementia · doi:10.1017/9781139924771.008 · Cited by 7 · see citing works
- Authors
- DICKSON, D. W.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- DICKSON, DENNIS W.
- ORCID
- DICKSON, DENNIS W.
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-04
- Volume
- 56
- Issue
- 4
- Pages
- 321-339
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W2012215271
- Cited by
- 753
- References
- 0
- Citations by year
- 2026: 5 · 2025: 18 · 2024: 29 · 2023: 21 · 2022: 21 · 2021: 19 · 2020: 25 · 2019: 18 · 2018: 21 · 2017: 25 · 2016: 27 · 2015: 19 · 2014: 21 · 2013: 26 · 2012: 22
- FWCI
- 22.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ag006803-11)
- U.S. Public Health Service (NIA 03949)
- National Institute on Aging (AG-06803)
- 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 plaques, Alzheimer disease pathogenesis, APP processing, amyloid-beta 42, Aβ40, neuritic plaques, microglial activation, reactive astrocytes, neuroinflammation, paired helical filaments, dystrophic neurites, neurofibrillary degeneration, neurodegeneration, cerebral amyloid angiopathy, amygdala
- MeSH terms
- Aging, Alzheimer Disease, Amyloid, Animals, Apolipoproteins E, Brain, Humans, Neurites, Glycation End Products, Advanced
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