Soluble Aβ Promotes Wild-Type Tau Pathology In Vivo
Open accessAbstract
Growing evidence suggests that soluble Aβ species can drive Alzheimer disease (AD) pathogenesis by inducing a cascade of events including tau hyperphosphorylation, proteasome impairment, and synaptic dysfunction. However, these studies have relied largely on in vitro approaches to examine the role of soluble Aβ in AD. In particular, it remains unknown whether soluble Aβ oligomers can facilitate the development of human wild-type tau pathology in vivo. To address this question, we developed a novel transgenic model that expresses low levels of APP with the Arctic familial AD mutation to enhance soluble Aβ oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of β-site APP cleaving enzyme (BACE) in these ArcTau mice decreases soluble Aβ oligomers, rescues cognition, and, more importantly, reduces tau accumulation and phosphorylation. Notably, BACE reduction decreases the postsynaptic mislocalization of tau in ArcTau mice and reduces the association between NMDA receptors and PSD-95. These studies provide critical in vivo evidence for a strong mechanistic link between soluble Aβ, wild-type tau, and synaptic pathology.
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Findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP.
“These findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP [7,8,9,10,11,12,13,36].”
From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [36]
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Experimental — accuracy not yet measuredHuman data and animal model data suggest a causal upstream role for Aβ in the pathogenesis of AD.
“These human data and animal model data [100] suggest a causal upstream role for Aβ in the pathogenesis of AD”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [100]
Abundant human and animal data implicate A and T in the primary pathogenesis of AD.
“Abundant human and animal data implicate A and T in the primary pathogenesis of AD [9,100], including the observation that the age-related exponential increase in prevalence of A (by biomarkers and neuropathology) anticipates the age-related exponential increase in prevalence of clinically defined possible/probable “AD” by around 15 years [53,212].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [100]
Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis that lies upstream of tau-induced neurodegeneration.
“Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”
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References 31 · Cited by 123
Research works printed but not linked: 22
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- Authors
- Chabrier, M. A., Blurton-Jones, M., Agazaryan, A. A., Nerhus, J. L., Martinez-Coria, H., & LaFerla, F. M.
- Affiliations
- University of California, Irvine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-11-28
- Volume
- 32
- Issue
- 48
- Pages
- 17345-17350
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3586232
- OpenAlex
- W2101271930
- Cited by
- 123
- References
- 31
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 1 · 2022: 7 · 2021: 4 · 2020: 11 · 2019: 9 · 2018: 14 · 2017: 11 · 2016: 15 · 2015: 16 · 2014: 12 · 2013: 16
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, Irvine
- National Institute on Aging (P01AG000538, AG027544, AG 16573, K01AG029378, AG 00538, PPG AG 00538, P50AG016573, AG-029378, F31AG039968, R01AG027544)
- 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
- soluble amyloid-beta oligomers, Alzheimer's disease, tau phosphorylation, synaptic dysfunction, transgenic mouse model
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Learning, Memory, Mice, Transgenic, Neurons, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Mice
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