A lattice structure hidden just beneath the surface of neurons may act as a critical control point for how cells absorb nutrients and toxic proteins, Penn State researchers have found. The discovery could open new avenues for slowing Alzheimer's disease before symptoms appear.
The structure, called the membrane-associated periodic skeleton or MPS, is built from repeating rings of proteins and sits beneath the neuronal cell surface. Scientists knew it helped neurons maintain their shape, but new research shows it plays a far more active role: controlling where and when substances enter the cell.
Ruobo Zhou, an assistant professor at Penn State and corresponding author on the study published in Science Advances, explained the significance. "When endocytosis goes wrong, protein aggregation builds up in the brain, which is the hallmark of neurodegenerative diseases such as Alzheimer's and Parkinson's," Zhou said.
To map the MPS at work, researchers used super-resolution microscopy, technology that can reveal structures about 10,000 times smaller than a human hair. They grew neurons in laboratory dishes, tagged specific proteins so they could be tracked, and exposed the cells to different molecules while observing how material entered them.
The results revealed that the MPS functions like a cellular gatekeeper, slowing the absorption of nutrients and other materials into the cell. When researchers damaged the lattice, neurons began absorbing material much faster, confirming that an intact MPS normally restricts what enters.
But the team uncovered something more troubling: the structure can trigger its own collapse. When neurons absorbed material too quickly, the faster uptake activated molecular signals that directed proteins to break apart sections of the skeleton. This opened additional entry points and allowed even more material inside, creating a destructive feedback loop.
The researchers then mimicked the early stages of Alzheimer's disease by making neurons produce higher levels of amyloid precursor protein (APP), a key marker of the condition. When they weakened the MPS in these cells, APP entered faster and converted into amyloid-B42, a toxic fragment strongly linked to Alzheimer's. Neurons with damaged MPS accumulated dangerous levels of this harmful molecule and showed increased signs of cell death.
"In aging neurons or neurons under pathologic conditions, the endocytosis of toxic proteins was enhanced, which caused stressing conditions, ultimately leading to neuron death," said Jinyu Fei, a graduate student and lead author on the study.
The implications are significant. The MPS appears to serve as a protective barrier by limiting how much toxic protein enters neurons. Because this structure is known to deteriorate during aging and neurodegenerative disease, its breakdown could push neurons into a damaging spiral: more amyloid enters, the skeleton weakens further, and eventually cells die.
"Preserving or stabilizing the MPS might offer a way to slow the early, hidden cellular changes that precede Alzheimer's symptoms," Fei said. If the MPS can be protected or reinforced, researchers believe it could form the basis of new treatments targeting neurodegenerative diseases before visible damage occurs.
Author Jessica Williams: "This is the kind of pre-symptom intervention science has been chasing for years, and finding a physical structure to target makes it actually tangible."
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