More Than Amyloid Plaques in the Alzheimer’s Brain: Study Identifies “Mitochondrial Plaques”

The most prominent pathological hallmarks of Alzheimer’s disease have long been extracellular amyloid protein plaques and intracellular tau protein tangles. Researchers have now identified another structure within this picture: large numbers of mitochondria clustering within neurites to form what they call “mitochondrial plaques.” The finding places neurons’ energy systems and cellular waste-processing mechanisms along the same causal line of investigation in the disease.

The research team used APP/PSEN1 Alzheimer’s mice carrying the mt-Keima mitophagy reporter system to track whether mitochondria entered the acidic lysosomal environment. Imaging revealed large aggregates within neurites that contained both acidic mitochondria located inside lysosomes and mitochondria that had not yet entered lysosomes or had not been sufficiently acidified. Similar structures were also observed in another mouse model, 5xFAD, indicating that the phenomenon is not unique to a single model.

Further analysis indicated that these aggregates were mostly located in swollen, degenerating neurites. Abnormal mitochondria appeared to accumulate there first, with lysosomes subsequently recruited to process them; however, mitophagy was not successfully completed. In other words, although the clearance system had been activated, lysosomal degradation capacity at the final stage was insufficient, leaving mitochondrial debris at different stages of processing.

The relationship between mitochondrial plaques and conventional amyloid plaques is not uniform. In the study, some mitochondrial plaques formed mixed plaques with amyloid-β, while others appeared independently at earlier stages; higher levels of amyloid precursor protein APP could also be detected within them. This supports the possibility that the two pathologies may be intertwined, but it does not yet prove that mitochondrial plaques initiate or accelerate extracellular amyloid deposition.

The researchers also found comparable mitochondrial aggregate structures in postmortem brain tissue from patients with Alzheimer’s disease, while the healthy control group analyzed in the preprint did not show the same features. This human evidence strengthens the association of the finding with the disease, but postmortem tissue can provide only a snapshot at a specific point in time and cannot determine whether mitochondrial plaques form before symptoms, accumulate as the disease worsens, or are merely a downstream consequence of neurodegeneration.

The work therefore proposes a new direction for investigation: rather than addressing only amyloid proteins that have already been deposited, could restoring mitochondrial transport, the autophagy process, or lysosomal degradation capacity prevent the intracellular neurite “traffic jam” from expanding? However, the current evidence comes mainly from animal models and postmortem tissue and has not yet shown that clearing mitochondrial plaques can improve cognition or slow the disease.

The research team’s next step is to identify biomarkers capable of detecting mitochondrial plaques in living organisms and to screen for drugs that can prevent their formation or promote their clearance. Until such tools are available, “mitochondrial plaques” are better regarded as a newly proposed pathological entity and research target, rather than a clinical indicator that can already be used for diagnostic or treatment decisions.