Swelling Along Brain’s Axons May Be True Culprit in Alzheimer’s Disease

Summary: The formation of plaques can cause the accumulation of spheroid-shaped swellings along axons near the amyloid plaque deposits. The swellings are caused by lysosomes, which digest cellular waste. As the swelling enlarges, it can block the transmission of signals from one area of the brain to another.

Source: Yale

The formation of amyloid plaques in the brain is a hallmark of Alzheimer’s disease. But drugs designed to reduce accumulations of these plaques have so far yielded, at best, mixed results in clinical trials.

Yale researchers have found, however, that swelling caused by a byproduct of these plaques may be the true cause of the disease’s debilitating symptoms, they report Nov. 30 in the journal Nature. And they identified a biomarker that may help physicians better diagnose Alzheimer’s and provide a target for future therapies.

According to their findings, each formation of plaque can cause an accumulation of spheroid-shaped swellings along hundreds of axons—the thin cellular wires that connect the brain’s neurons—near amyloid plaque deposits.

The swellings are caused by the gradual accumulation of organelles within cells known as lysosomes, which are known to digest cellular waste, researchers found. As the swellings enlarge, researchers say, they can blunt the transmission of normal electrical signals from one region of the brain to another.

This pileup of lysosomes, the researchers say, causes swelling along axons, which in turn triggers the devasting effects of dementia.

“We have identified a potential signature of Alzheimer’s which has functional repercussions on brain circuitry, with each spheroid having the potential to disrupt activity in hundreds of neuronal axons and thousands of interconnected neurons,” said Dr. Jaime Grutzendler, the Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience at the Yale School of Medicine and senior author of the study.

Further, the researchers discovered that a protein in lysosomes called PLD3 caused these organelles to grow and clump together along axons, eventually leading to the swelling of axons and the breakdown of electrical conduction.

When they used gene therapy to remove PLD3 from neurons in mice with a condition resembling Alzheimer’s disease, they found that this led to a dramatic reduction of axonal swelling. This, in turn, normalized the electrical conduction of axons and improved the function of neurons in the brain regions linked by these axons.

The researchers say PLD3 may be used as a marker in diagnosing the risk of Alzheimer’s disease and provide a target for future therapies.

“It may be possible to eliminate this breakdown of the 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

Author: Bill Hathaway
Source: Yale
Contact: Bill Hathaway – Yale
Image: The image is in the public domain

Original Research: Open access.
“PLD3 affects axonal spheroids and network defects in Alzheimer’s disease” by Peng Yuan et al. Nature Communications

See also

Abstract

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 prominent contributors to neural network dysfunction.

Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting 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 linked with Pld3—a potential Alzheimer’s-disease-associated risk gene that encodes a lysosomal protein that is highly enriched in axonal spheroids.

Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function.

Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independent of amyloid removal.