Summary: Researchers identified a novel form of neuropathology in Alzheimer’s disease: mitochondrial plaques.
The study demonstrates that these intracellular, mitochondrially localized plaques emerge in both preclinical models and human post-mortem brain tissue. Distinct from classic extracellular beta-amyloid (A-beta) plaques, mitochondrial plaques accumulate high levels of amyloid precursor protein (APP) and appear to form independently during the earliest stages of neurodegeneration, potentially preceding traditional A-beta plaque aggregation.
Because these structures directly impair intracellular neuronal machinery, they represent an unrecognized driver of disease progression and an early therapeutic target for slowing or preventing Alzheimer’s pathology.
Key Facts
- Novel Neuropathological Entity: Identifies “mitochondrial plaques” as a distinct pathology in Alzheimer’s disease, present in both preclinical animal models and human brain tissue.
- Precedes Classic Amyloid Pathology: Mitochondrial plaques form independently of extracellular beta-amyloid plaques and may develop during the earliest, preclinical stages of Alzheimer’s progression.
- Intracellular APP Accumulation: These newly recognized structures harbor dense concentrations of amyloid precursor protein (APP), the direct biochemical precursor to cytotoxic beta-amyloid peptides.
- Direct Neuronal Impact: Unlike classic A-beta plaques that deposit in the extracellular space, mitochondrial plaques reside within the organelle architecture of neurons, directly compromising cellular energy production and survival.
- Plaque Seeding Hypothesis: As Alzheimer’s advances, mitochondrial plaques frequently colocalize with traditional extracellular plaques, suggesting they may act as early intracellular seeds or catalysts for broader amyloid pathology.
Source: University of Minnesota
A University of Minnesota research team has identified a type of plaque that represents a new potential therapeutic target for Alzheimer’s disease.
The findings were recently published in Nature Neuroscience.
Alzheimer’s disease is a devastating neurodegenerative disorder affecting millions of individuals worldwide. Scientists have long known that two hallmarks of the disease are beta-amyloid (Aβ) plaques and neurofibrillary tangles, which damage and kill brain cells over time.
The researchers identified a newly recognized type of brain plaque, called mitochondrial plaques, in both preclinical models of Alzheimer’s disease and human brain tissue. Mitochondrial plaques appear to form independently of traditional amyloid plaques and may emerge at the earliest stages of the disease, possibly even before beta-amyloid plaques begin to develop.
The researchers also found that mitochondrial plaques contain high levels of amyloid precursor protein, which is the molecule that gives rise to beta-amyloid. As the disease progresses, mitochondrial plaques frequently appear alongside traditional amyloid plaques, suggesting they may help drive the formation of those hallmark brain changes.
“This discovery identifies mitochondrial plaques as a previously unrecognized feature of Alzheimer’s disease,” said Paul Robbins, PhD, professor in the University of Minnesota Medical School and associate director of the Masonic Institute on the Biology of Aging and Metabolism. “By understanding how these plaques form and contribute to disease progression, we may be able to develop new strategies to slow or even prevent Alzheimer’s disease.”
“Unlike the amyloid plaques found outside brain cells, these plaques appear to directly affect neurons, which make them a potential new target for Alzheimer’s disease treatments,” said Xiuli Dan, first author and research assistant professor.
Next steps include the identification of biomarkers of mitochondrial plaques and screening for drugs that can prevent their accumulation.
Funding: This work was supported in part by the Intramural Program of the National Institute on Aging and National Institutes of Health [grant numbers U19 AG056278 and U54 AG079754] (PDR). This work was supported in part by the 2023 National Academy of Medicine Healthy Longevity Catalyst Award.
Key Questions Answered:
A: Traditional amyloid plaques are extracellular deposits composed of aggregated beta-amyloid peptides that collect outside brain cells. In contrast, mitochondrial plaques form directly inside neurons within the mitochondria, contain high concentrations of intact amyloid precursor protein (APP), and appear prior to classic extracellular plaque buildup.
A: Because mitochondrial plaques emerge at the very beginning of the disease process, potentially before standard beta-amyloid plaques are detectable, identifying biomarkers specific to these organelle-level changes could enable much earlier diagnosis before widespread structural brain damage occurs.
A: The research team is focusing on developing specific biological markers to detect mitochondrial plaques in living patients and conducting drug screening campaigns to identify small molecules that can block or remove these intracellular accumulations before they trigger irreversible neuronal death.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Alexandra Smith
Source: University of Minnesota
Contact: Alexandra Smith – University of Minnesota
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease” by Xiuli Dan, Deborah L. Croteau, Wenlong Liu, Xixia Chu, Ross A. McDevitt, Paul D. Robbins & Vilhelm A. Bohr. Nature Neuroscience
DOI:10.1038/s41593-026-02390-1
Abstract
Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease
Dysfunctional mitophagy is proposed as a key component of Alzheimer’s disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs).
The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria.
MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.
