Summary: Plaque formation can cause spheroid-shaped swellings to build up along axons near amyloid plaque deposits. The swellings are caused by lysosomes, which digest cellular waste. As the swelling grows, it can block the transmission of signals from one area of the brain to another.
The formation of amyloid plaques in the brain is a hallmark of Alzheimer’s disease. But drugs designed to reduce the buildup of these plaques have so far had, at best, mixed results in clinical trials.
Yale researchers have found, however, that swelling caused by a byproduct of these plaques may be the real cause of the disease’s debilitating symptoms, they report Nov. 30 in the journal. Nature. And they identified a biomarker that could help doctors better diagnose Alzheimer’s disease and provide a target for future therapies.
According to their findings, each plaque formation can cause spheroid-shaped swellings to build up along hundreds of axons – the thin cellular threads that connect neurons in the brain – near amyloid plaque deposits.
The swellings are caused by the gradual buildup of organelles in cells called lysosomes, which are known to digest cellular waste, the researchers found. According to the researchers, as the swellings get bigger, they can dampen the transmission of normal electrical signals from one region of the brain to another.
This stacking of lysosomes, the researchers say, causes swelling along the axons, which in turn triggers the devastating effects of dementia.
“We have identified a potential signature of Alzheimer’s disease that has functional implications for brain circuitry, with each spheroid having the potential to disrupt the activity of hundreds of neuronal axons and thousands of interconnected neurons,” said the Dr. Jaime Grutzendler, Dr. Harry M. Zimmerman, and Dr. Nicholas and Viola Spinelli, professor of neurology and neuroscience at Yale School of Medicine and lead author of the study.
Additionally, the researchers found that a protein in lysosomes called PLD3 causes these organelles to grow and clump together along the axons, ultimately leading to the axons swelling and breaking electrical conduction.
When they used gene therapy to knock out PLD3 from neurons in mice with Alzheimer’s-like disease, they found it led to a dramatic reduction in axonal swelling. This, in turn, normalized the electrical conduction of axons and improved the function of neurons in brain regions linked by these axons.
The researchers say that PLD3 can be used as a marker in the diagnosis of Alzheimer’s disease risk and provide a target for future therapies.
“It may be possible to eliminate this degradation of electrical signals in axons by targeting PLD3 or other molecules that regulate lysosomes, independent of the presence of plaques,” Grutzendler said.
About this Alzheimer’s disease research news
Original research: Free access.
“PLD3 affects axonal spheroids and network defects in Alzheimer’s disease” by Peng Yuan et al. Nature Communication
PLD3 affects axonal spheroids and network defects in Alzheimer’s disease
The precise mechanisms that lead to cognitive decline in Alzheimer’s disease are unknown. Here, we identify amyloid plaque-associated axonal spheroids as important contributors to neural network dysfunction.
Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease exhibits severe disruption of long-range axonal connectivity. This disturbance is caused by action potential conduction blocks due to the enlargement of spheroids acting as electrical current sinks in a size-dependent manner.
Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked to pld3—a potential risk gene associated with Alzheimer’s disease that codes for a lysosomal protein highly enriched in axonal spheroids.
Neuronal overexpression of pld3 led to accumulation of endolysosomal vesicles and enlargement of spheroids, which worsened axonal conduction blockades. However, pld3 deletion reduced the size of endolysosomal vesicles and spheroids, resulting in improved electrical conduction and neural network function.
Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neuronal circuit abnormalities in Alzheimer’s disease, independent of amyloid clearance.