Summary: Plaque formation can lead to the accumulation of spherical swellings along axons near amyloid plaque deposits. Swelling is caused by lysosomes that digest cellular waste. As the swelling gets bigger, 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 accumulation of these plaques have so far produced mixed results in clinical trials.
However, Yale researchers have found that swelling, a byproduct of these plaques, may be the real cause of the disease’s debilitating symptoms, they report in the Nov. 30 issue of the journal. nature. And they identified a biomarker that could help doctors better diagnose Alzheimer’s and provide a target for future treatments.
According to their findings, each plaque formation can lead to the accumulation of spherical swellings along hundreds of axons, the thin cellular wires that connect neurons in the brain near amyloid plaque deposits.
The researchers found that the swelling is caused by the gradual accumulation of organelles in cells known as lysosomes, which are known to digest cellular waste. As the swelling grows, the researchers say, it can block the transmission of normal electrical signals from one area of the brain to another.
According to the researchers, this accumulation of lysosomes causes swelling along the axons, which has devastating effects in dementia.
“We have identified a potential signature of Alzheimer’s disease that has functional consequences for brain circuitry, capable of disrupting the activity of hundreds of individual spherical neuron axons and thousands of interconnected neurons,” said Dr. James Gratzendler, MD, Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli, professor of neurology and neuroscience at Yale School of Medicine and senior author of the study.
And, the researchers found, a protein in the lysosomes called PLD3 caused these organelles to grow and clump together along the axons, eventually leading to swelling of the axons and breakdown of electrical conduction.
When they used gene therapy to remove PLD3 from neurons in mice with a condition similar to Alzheimer’s disease, they found that this led to a dramatic reduction in axonal swelling. This, in turn, normalized the electrical conduction of the axons and improved the activity of neurons in the brain regions connected by these axons.
The researchers say PLD3 could be used as a marker of Alzheimer’s disease risk and provide a target for future treatments.
“Targeting PLD3 or other molecules that regulate lysosomes may be able to eliminate this breakdown of electrical signals in axons, independent of the presence of plaques,” Grutzendler said.
This is research news about Alzheimer’s disease
Author: Bill Hathaway
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. Natural communication
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PLD3 affects axonal spheroids and network defects in Alzheimer’s disease
The exact mechanisms leading to cognitive decline in Alzheimer’s disease are unknown. Here we identify amyloid-plaque-associated axonal vesicles as dominant contributors to neuronal network dysfunction.
Using intravital calcium and voltammetry imaging, we show that a mouse model of Alzheimer’s disease exhibits severe disruption of long-range axonal connectivity. This disruption is caused by action-potential conduction blockages due to enlarging spheres that act as current sinks in a size-dependent manner.
Spheroid growth was associated with age-dependent accumulation of large endolysosomal vesicles and mechanistically linked Pld3—A risk gene associated with Alzheimer’s disease encoding a lysosomal protein highly enriched in axial globules.
Overexpressing neurons Pld3 Axonal conduction block worsened endolysosomal vesicle accumulation and spheroid enlargement. In contrast, Pld3 Deletion reduced endolysosomal vesicle and spheroid size, thereby improving electrical conductance and neural network function.
Thus, targeted modulation of endolysosomal biogenesis in neurons may reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease independently of amyloid clearance.