Research: Neurodegeneration

The problem

Alzheimer’s disease is a common neurodegenerative disorder marked by amyloid-β, yet much of its mechanism remains unclear. Amyloid precursor protein (APP) has long been studied as the precursor of amyloid-β, but the physiological functions of APP itself in neurons have not been fully understood. In Parkinson’s disease, mitochondrial and lysosomal dysfunction have long been implicated, without a detailed mechanism.

What we found — failed clearance of nuclear-derived waste

In a 2026 PNAS paper we used cultured cells, human iPSC-derived neurons, mouse brain, and postmortem Alzheimer’s brains to show that APP helps maintain homeostasis by discharging nuclear-derived waste generated upon nuclear damage through lysosomal exocytosis. Reducing APP caused intracellular accumulation of that waste, inflammation and cell death. Wild-type APP rescued these defects; familial Alzheimer’s APP variants did not. The same pattern held in mouse brain under DNA damage. In patient brains we observed abnormal nuclear morphology, cytoplasmic nuclear-derived waste, increased DNA damage, and reduced APP per neuron. These results indicate that APP is not merely a source of amyloid-β, but may also act as a protective molecule that shields neurons from nuclear stress. Access to well-curated human disease brain is one strength of this laboratory.

Paper: Dougnon et al., Proc. Natl. Acad. Sci. USA, 2026. doi:10.1073/pnas.2524190123 / BRI commentary

What we found — leakage of mitochondrial DNA

In Nature Communications (2021) we reported that mitochondrial DNA leaking into the cytosol induces cytotoxicity and neurodegeneration in cell and zebrafish models of Parkinson’s disease. Loss of PINK1, GBA or ATP13A2 increased cytosolic mtDNA, type I interferon responses and cell death. Overexpression of DNase II or reduction of IFI16 ameliorated these phenotypes; human DNase II also improved motor dysfunction and dopaminergic degeneration in gba-mutant zebrafish. Cytosolic mtDNA and IFI16 accumulated in lesioned regions of postmortem Parkinson’s brains.

Paper: Matsui et al., Nat. Commun., 2021. doi:10.1038/s41467-021-23452-x / Press release (PDF)

Models and the link to human disease

We combine cultured cells, small fishes, mice and human postmortem brain. Mechanisms found in cells and animals can be tested in disease brains of the institute’s brain bank. We continue to deepen Parkinson’s disease work and to approach Alzheimer’s disease, ALS and multiple system atrophy from new angles.