Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45-230 transgenic mice
Open accessAbstract
The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17kDa tau₄₅₋₂₃₀ fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau₄₅₋₂₃₀ and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau₄₅₋₂₃₀ mice when compared to wild-type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-d-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau₄₅₋₂₃₀ is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ.
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Tau45-230 is neurotoxic, and can induce synaptic and cognitive impairment.
“a recent study utilizing tau45–230 transgenic mice indicates that tau45–230 is neurotoxic, and can induce synaptic and cognitive impairment [204, 205, 209].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [209]
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- Authors
- Lang, A. E., Riherd Methner, D. N., & Ferreira, A.
- Affiliations
- Northwestern University (US)
- ORCID
- Ferreira, A.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 275
- Pages
- 322-339
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC4122686
- OpenAlex
- W2078770779
- Cited by
- 35
- References
- 79
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 1 · 2014: 1
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (NS39080)
- Northwestern University
- 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
- tauopathy, Alzheimer's disease, calpain cleavage, neurodegeneration, synaptic loss, hippocampal pyramidal neurons, NMDA receptor subunits, behavioral abnormalities, transgenic mice
- MeSH terms
- Animals, Behavior, Animal, Disease Models, Animal, Hippocampus, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Synapses, Blotting, Western, tau Proteins, Maze Learning, Reverse Transcriptase Polymerase Chain Reaction, Tauopathies, Mice
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