Tau Positive Neurons Show Marked Mitochondrial Loss and Nuclear Degradation in Alzheimer's Disease
Abstract
Background: Alzheimer's disease (AD) pathology consists of intraneuronal neurofibrillary tangles, made of hyperphosphorylated tau and extracellular accumulation of beta amyloid (Aβ) in Aβ plaques. There is an extensive debate as to which pathology initiates and is responsible for cellular loss in AD. Methods: Using confocal and light microscopy, post mortem brains from control and AD cases, an antibody to SOD2 as a marker for mitochondria and an antibody to all forms of tau, we analyzed mitochondrial density in tau positive neurons along with nuclear degradation by calculating the raw integrative density. Results: Our findings showed an extensive staining of aggregated tau in cell bodies, dystrophic neurites and neurofilaments in AD with minimal staining in control tissue, along with a marked decrease in mitochondria in tau positive (tau+) neurons. The control or tau negative (tau-) neurons in AD contained an even distribution of mitochondria, which was greatly diminished in tau+ neurons by 40%. There were no significant differences between control and tau- neurons in AD. Tau+ neurons showed marked nuclear degradation which appeared to progress with the extent of tau aggregation. The aggregated tau infiltrated and appeared to break the nuclear envelope with progressively more DNA exiting the nucleus and associating with the aggregated intracellular tau. Conclusion: We report that the mitochondrial decrease is likely due to a decrease in the protein synthesis rather than a redistribution of mitochondria because of the decreased axonal transport. We suggest that the decrease in mitochondria and nuclear degradation are key mechanisms for the neuronal loss seen in AD.
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In vitro studies using soluble phospho-tau oligomers find substantial alterations in nuclear-cytoplasmic transport.
“Not only is there clear morphological evidence of nuclear alterations in AD, but also, in vitro studies using soluble phospho-tau oligomers as a perturbant find substantial alterations in nuclear–cytoplasmic transport (e.g., 31, 33, 37, 54).”
From All the Tau We Cannot See (2023) · cites this paper as [54]
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“AD samples have markedly fewer mitochondria in Tau-positive neurons than control tissues do [76], which may be associated with the mitochondrial transportation impairment.”
BackgroundZn2+ Aggravates Tau Aggregation and Neurotoxicity
Li, X., Du, X., & Ni, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030487 · Cited by 48 · see citing works
“Thus, we performed immunofluorescence analyses by staining for MAP-2 in primary neuronal cultures (Figure 7) to directly view the growth status of hippocampal neurons (Figure 7A–”
InfluentialHyman, B. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-023749 · Cited by 39 · see citing works
“Not only is there clear morphological evidence of nuclear alterations in AD, but also, in vitro studies using soluble phospho-tau oligomers as a perturbant find substantial alterations in nuclear–cytoplasmic transport (e.g., 31, 33, 37, 54).”
Madireddy, S., & Madireddy, S. (2019) · Journal of Neuroscience and Neurological Disorders · doi:10.29328/journal.jnnd.1001026 · Cited by 16 · see citing works
“In this regard, mitochondrial dysfunction is a key protagonist in the pathogenesis of AD [12,65,66].”
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“, 2011), suggesting that tau plays a key role in the mitochondrial loss observed in AD (Wee et al., 2018).”
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“Mitochondrial loss and distribution deficits of mitochondria were observed in AD brain [25,26], and mitochondrial fragmentation was observed in hippocampal neurons of AD patients resulting in ATP depletion [27].”
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“Nevertheless, the view that mitochondria constitute a central target of AD associated pathogenic proteins is unequivocal (Wee et al. 2018).”
Hebisch, M., Kamin, V., Cenini, G., Piazzesi, A., Bertan, F., Weykopf, B., Schlee, J., Kaniyappan, S., Washicosky, K. J., Kim, D. Y., et al. (2026) · Cell Reports Methods · doi:10.1016/j.crmeth.2026.101365 · Cited by 1 · see citing works
“62 Such a selective mitochondrial pathology also serves as an internal control for potential side effects of the Tet-On system since Dox has been reported to affect mitochondrial translation at very high concentrations.”
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Self-citationZhuang, H., Zhou, L., Wang, X. H., Tanzi, E. B., Li, Y., Spincemaille, P., Kovanlıkaya, İ., Nguyen, T. D., Wang, Y., & Chiang, G. C.-Y. (2026) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.70442
“13,48 Global oxygen metabolism was measured in both amyloid/amyloid precursor protein and tau AD mouse models using MRI techniques, and the tau model showed decreased CMRO 2 , whereas the amyloid model did not.”
- Authors
- Wee, M., Chegini, F., Power, J. H. T., & Majd, S.
- Affiliations
- Flinders University (AU)
- Corresponding author
- Power, John H.T.
- ORCID
- Majd, Shohreh
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2018-08-15
- Volume
- 15
- Issue
- 10
- Pages
- 928-937
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2808657046
- Cited by
- 19
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 4
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Alzheimer's disease, tau aggregation, neurofibrillary tangles, mitochondrial loss, nuclear degradation, neuronal loss, manganese superoxide dismutase, dystrophic neurites, neurofilaments, nuclear envelope breakdown, protein synthesis, axonal transport
- MeSH terms
- Superoxide Dismutase 2, Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Brain, Cell Nucleolus, Female, Humans, Indoles, Male, Middle Aged, Mitochondria, Neurons, Superoxide Dismutase, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Microscopy, Confocal
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