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Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease

Xiuli Dan1,2, Deborah L Croteau1,3, Wenlong Liu4

  • 1Section on DNA Repair, National Institute on Aging, NIH, Baltimore, MD, USA.

Nature Neuroscience
|July 29, 2026
PubMed

Insights

Mitochondrial plaques (MPs), a new pathological structure in Alzheimer's disease (AD), were discovered in AD model mice and human brains. These plaques result from dysfunctional mitophagy and impaired lysosomal function in neurons.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pathology

Background:

  • Dysfunctional mitophagy is implicated in Alzheimer's disease (AD) pathology.
  • Direct in vivo evidence and mechanistic insights into mitophagy's role in AD are limited.

Purpose of the Study:

  • To investigate the in vivo role of mitophagy in Alzheimer's disease.
  • To identify and characterize novel pathological structures associated with AD.

Main Methods:

  • Utilized AD model mice (APP/PSEN1/mt-Keima) expressing a mitophagy reporter.
  • Analyzed mitochondrial accumulation and lysosomal function in neuronal processes.
  • Examined postmortem human AD brains for pathological features.

Main Results:

  • Identified a previously unrecognized pathological structure termed mitochondrial plaques (MPs) in AD model mice.
  • MPs are characterized by the accumulation of acidic and neutral mitochondria due to impaired mitophagy and lysosomal function.
  • MPs were found to co-develop with amyloid plaques but can also emerge independently, and were present in 5xFAD mice and human AD brains.

Conclusions:

  • Mitochondrial plaques (MPs) represent a novel pathological entity in Alzheimer's disease.
  • Dysfunctional mitophagy and impaired lysosomal degradation contribute to MP formation.
  • MPs are present in both mouse models and human AD brains, suggesting their significance in AD pathogenesis.

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