Summary: Researchers have identified a previously unrecognized neuropathological structure in Alzheimer’s disease: mitochondrial plaques.
A team at the University of Minnesota reports that these intracellular, mitochondrially localized plaques appear in preclinical models and in human post-mortem brain tissue. Unlike the well-known extracellular beta-amyloid (Aβ) plaques, mitochondrial plaques accumulate high levels of intact amyloid precursor protein (APP) inside neuronal mitochondria. Evidence suggests they form independently and at very early stages of neurodegeneration, potentially before the appearance of classical extracellular Aβ deposits.
Because mitochondrial plaques arise within the organelles responsible for cellular energy and metabolic regulation, they directly impair neuronal function and survival. This positions them as an unrecognized driver of disease progression and a promising target for early diagnosis and intervention.
Key Facts
- Distinct pathological entity: Mitochondrial plaques are identified as a separate lesion type in Alzheimer’s disease, verified in multiple animal models and in human brain tissue.
- Early occurrence: These plaques can form independently of extracellular Aβ deposits and may appear during the earliest, preclinical stages of Alzheimer’s progression.
- Intracellular APP accumulation: Mitochondrial plaques contain dense concentrations of APP, the precursor molecule from which toxic Aβ peptides are generated.
- Direct cellular impact: Located inside neurons, within mitochondrial architecture, these plaques compromise energy production and cellular homeostasis rather than depositing externally.
- Possible seeding role: As disease progresses, mitochondrial plaques often colocalize with extracellular amyloid, suggesting they may act as intracellular seeds or catalysts that promote broader amyloid pathology.
Source: University of Minnesota
Research teams at the University of Minnesota have described mitochondrial plaques as a potential new therapeutic target for Alzheimer’s disease.
The findings were published in Nature Neuroscience and outline both mechanistic observations from animal models and confirmatory evidence in human post-mortem brain samples.
Alzheimer’s disease remains a leading cause of dementia worldwide. Historically, two hallmark lesions—extracellular beta-amyloid plaques and intracellular neurofibrillary tangles—have defined pathological staging. The discovery of mitochondrial plaques adds an organelle-level lesion to that framework and suggests additional pathways by which neuronal function is disrupted.
In laboratory models, mitochondrial plaques show substantial buildup of APP within mitochondria and nearby neuronal processes. These accumulations attract lysosomal components in an attempted degradative response, but impaired lysosomal function prevents complete clearance. The resulting persistent accumulation includes both neutral and acidic mitochondria, forming a distinctive plaque structure.
As disease evolves, mitochondrial plaques frequently appear alongside extracellular amyloid deposits, creating mixed lesion types. Their early emergence in models and detection in human tissue raise the possibility that mitochondrial plaques precede and help drive extracellular plaque formation, making them a potential early biomarker and therapeutic target.
“This discovery identifies mitochondrial plaques as a previously unrecognized feature of Alzheimer’s disease,” said Paul Robbins, PhD, professor at the University of Minnesota Medical School. “Understanding how these plaques form and how they contribute to neuronal dysfunction could open new approaches to slow or prevent disease progression.”
Xiuli Dan, the study’s first author, noted that because these plaques form inside neurons and within mitochondria, they present a direct threat to cellular energy systems and may be more readily targeted by treatments that reach intracellular compartments.
Research priorities now include discovering biomarkers that reliably detect mitochondrial plaques in living patients and screening compounds that prevent their formation or promote their safe clearance before irreversible neuronal loss occurs.
Funding: This work was supported in part by the Intramural Program of the National Institute on Aging and National Institutes of Health (including grants U19 AG056278 and U54 AG079754) and by the 2023 National Academy of Medicine Healthy Longevity Catalyst Award.
Key Questions Answered
A: Classic amyloid plaques are extracellular accumulations of aggregated Aβ peptides found outside neurons. Mitochondrial plaques form inside neurons, localize to mitochondria, and contain high concentrations of intact APP. They appear earlier in disease models and likely impair intracellular function directly.
A: Because mitochondrial plaques can emerge at very early stages—possibly before extracellular Aβ is detectable—biomarkers that detect these organelle-level changes could enable earlier diagnosis and intervention, potentially before widespread neuronal loss.
A: The research team aims to identify biological markers of mitochondrial plaques suitable for clinical detection and to run drug screens for agents that prevent or clear these intracellular accumulations, protecting neurons from energy failure and degeneration.
Editorial Notes
- This article was edited by an editor at Neuroscience News.
- The journal paper was reviewed in full by editorial staff.
- Additional context was provided by the reporting team to aid clarity and reader understanding.
About this Alzheimer’s disease research news
Author: Alexandra Smith
Source: University of Minnesota — Contact: Alexandra Smith, University of Minnesota
Image: Image credit 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 implicated as a central feature of Alzheimer’s disease pathology, but direct in vivo evidence and mechanistic clarity have been limited. Using AD model mice that express a mitophagy reporter (APP/PSEN1/mt-Keima), the researchers observed large accumulations of both acidic and neutral mitochondria within neuronal processes. These accumulations form a previously unrecognized pathological structure, termed mitochondrial plaques (MPs).
MP formation is driven by abnormal mitochondrial buildup. Lysosomal recruitment to these sites occurs as a compensatory, delayed response intended to promote degradation. However, lysosomal dysfunction prevents efficient mitophagy, so mitochondria persist in both neutral and acidic states, creating stable plaque-like structures.
MPs frequently co-develop with extracellular amyloid to create mixed plaques, but they can also arise independently at early disease stages. Importantly, MPs were identified not only in the APP/PSEN1 reporter mice but also in the 5xFAD AD mouse model and in postmortem human Alzheimer’s brains. These findings establish mitochondrial plaques as a novel pathological entity in Alzheimer’s disease and suggest new directions for early diagnosis and therapeutic development.