Swelling along the brain’s axons may be the real culprit in Alzheimer’s disease
Abstract: Plaque formation can cause the accumulation of spheroidal swellings along axons in the vicinity of amyloid plaque deposits. Swelling is caused by lysosomes, which digest cellular waste. As the swelling increases, it can block the transmission of signals from one area of the brain to another.
The formation of amyloid deposits in the brain is a hallmark of Alzheimer’s disease. But drugs intended to reduce the build-up of these plaques have so far produced mixed results in clinical trials, at best.
However, Yale researchers discovered that swelling caused by a byproduct of these plaques may be the real cause of the disease’s debilitating symptoms, they reported Nov. 30 in the journal Nature. And they have identified a biomarker that may help doctors better diagnose Alzheimer’s disease and provide a target for future therapies.
According to their findings, each plaque formation can cause a spheroid-like swelling to accumulate along hundreds of axons—the thin cell wires that connect brain neurons—near the amyloid plaque deposits.
The swelling is caused by the gradual accumulation of organelles inside cells known as lysosomes, which are known to digest cellular waste, the researchers found. As the swelling increases, the researchers say, it can dampen the transmission of normal electrical signals from one part of the brain to another.
This build-up of lysosomes, the researchers say, causes swelling along axons, which in turn triggers the devastating effects of dementia.
“We have identified a potential signature of Alzheimer’s disease that has functional consequences on brain circuits, with each spheroid having the potential to disrupt activity in hundreds of neuronal axons and thousands of interconnected neurons,” said Jaime Grutzendler, PhD, Harry M. Zimmerman, PhD, and Ph.D. Nicholas and Viola Spinelli, professor of neurology and neuroscience at Yale School of Medicine and senior author of the study.
Furthermore, the researchers found that a protein in the lysosomes called PLD3 caused these organelles to grow and shrink along the axon, eventually leading to swelling of the axon and failure of electrical conduction.
When they used gene therapy to remove PLD3 from neurons in mice with an Alzheimer’s-like condition, they found that it led to a dramatic reduction in axonal swelling. This in turn normalized the electrical conductivity of the axons and improved the function of neurons in the brain regions connected by those axons.
Researchers say PLD3 could be used as a marker to diagnose Alzheimer’s risk and provide a target for future therapies.
“It may be possible to eliminate this malfunction 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 research news
Original research: Open access.
“PLD3 affects axon spheroids and network defects in Alzheimer’s disease” Peng Yuan et al. Nature Communications
PLD3 affects axon spheroids and network defects in Alzheimer’s disease
The exact mechanisms leading to cognitive decline in Alzheimer’s disease are not known. Here, we identify axonal spheroids associated with amyloid plaque as prominent factors in neuronal network dysfunction.
Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease exhibits severe disturbances in long-range axonal connectivity. This disorder is caused by action potential conduction blockages due to the enlargement of spheroids that act as electric current sinks in a size-dependent manner.
Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically related to Pld3— a potential risk gene associated with Alzheimer’s disease encoding a lysosomal protein that is highly enriched in axon spheroids.
Neuron overexpression Pld3 it led to accumulation of endolysosomal vesicles and enlargement of spheroids, which exacerbated axonal conduction blocks. By contrast, Pld3 deletion reduced the size of endolysosomal vesicles and spheroids, leading to improved electrical conductivity and neural network function.
Therefore, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axon spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independent of amyloid clearance.