Neuron skeleton gates toxic Alzheimer's protein uptake
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- Penn State researchers identified the membrane-associated periodic skeleton (MPS), a lattice just beneath neuron surfaces, as a physical gatekeeper controlling nearly every major form of endocytosis, the process by which neurons absorb nutrients, signaling molecules, and membrane fragments
- Using super-resolution microscopy capable of imaging structures roughly 10,000 times smaller than the thickness of a human hair, the team observed that damaging the MPS caused laboratory neurons to absorb material much faster than normal, opening additional entry points for uptake
- Faster uptake fed back on the skeleton itself: increased endocytosis activated signaling that directed proteins inside neurons to cut sections of the lattice apart, weakening it further and accelerating absorption in what the authors describe as a self-reinforcing loop
- In a cellular model mimicking early Alzheimer's disease, weakening the MPS drove neurons to rapidly absorb amyloid precursor protein (APP), which was cleaved into amyloid-B42 — the toxic fragment strongly associated with Alzheimer's — and these cells accumulated more cell-death markers
- Jinyu Fei, lead author and Penn State chemistry graduate student, said preserving or stabilizing the MPS could offer a way to slow 'the early, hidden cellular changes that precede Alzheimer's symptoms,' positioning the lattice as a potential new therapeutic target
- Ruobo Zhou, assistant professor of chemistry, biochemistry and molecular biology, and biomedical engineering at Penn State and corresponding author on the study, originally co-discovered the MPS in 2013 as a postdoctoral researcher at Harvard; the findings were published in Science Advances with funding from the National Institutes of Health
Why it matters: Alzheimer's treatments today largely target the downstream amyloid plaques rather than the upstream cellular conditions that allow toxic proteins to accumulate in the first place. This study identifies the MPS lattice itself as a potential molecular target — drug developers could one day attempt to stabilize it to slow the earliest cellular changes that precede memory loss, although the work remains preclinical in cultured neurons.
