Overview: Plaque formation can cause the accumulation of spherical swellings along axons near amyloid plaque deposits. Swelling is caused by lysosomes that digest cellular waste products. As the swelling grows, it can block the transmission of signals from one area of the brain to another.
sauce: Yell
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 met with mixed results at best in clinical trials.
But researchers at Yale University have found that the swelling caused by these plaque byproducts may be the true cause of the disease’s debilitating symptoms, they said in the journal Nov. 30. reporting NatureAnd they identified biomarkers that may help doctors better diagnose Alzheimer’s disease and provide targets for future treatments.
They found that whenever plaques form, spherical swellings can accumulate along hundreds of axons (thin cellular wires that connect neurons in the brain) near amyloid plaque deposits. I have.
Researchers have discovered that the swelling is caused by the gradual build-up inside cells of organelles known as lysosomes, which are known to digest cellular waste. As the swelling grows, the researchers say, it can slow down the normal transmission of electrical signals from one area of the brain to another.
This lysosomal accumulation causes swelling along the axons, which causes the devastating effects of dementia, researchers say.
“We have identified a potential signature of Alzheimer’s disease that functionally affects brain circuits. Each spheroid disrupts the activity of hundreds of nerve axons and thousands of interconnected neurons. It’s possible,” said Dr. Jaime Grutzendler, Dr. Harry M. Zimmerman, Dr. Nicholas, and Viola Spinelli, professors of neurology and neuroscience at the Yale School of Medicine and senior authors of the study.
Furthermore, the researchers found that a protein within the lysosome called PLD3 causes these organelles to grow and aggregate along the axon, ultimately leading to axonal swelling and disruption of electrical conduction.
When they used gene therapy to remove PLD3 from neurons in mice with an Alzheimer’s-like condition, they found that axonal swelling was dramatically reduced. This normalized the electrical conduction of axons and improved the function of neurons in brain regions connected by these axons.
The researchers say PLD3 may be used as a marker in diagnosing Alzheimer’s disease risk and as a potential target for future therapies.
“It may be possible to eliminate this disruption of axonal electrical signaling by targeting PLD3 or other molecules that regulate lysosomes, independently of the presence of plaque,” Grutzendler said. .
About this Alzheimer’s Disease Research News
author: Bill Hathaway
sauce: Yell
contact: Bill Hathaway – Yale
image: image is public domain
Original research: open access.
“PLD3 influences axonal spheroids and network defects in Alzheimer’s diseaseby Pengyuan et al. Nature Communications
See also
Overview
PLD3 influences 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 axonal spheroids associated with amyloid plaques as a prominent cause of neural network dysfunction.
Using in vivo calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease exhibits profound disruption of long-distance axonal connections. This disruption is caused by action potential conduction blockade due to spheroid expansion that acts as a current sink in a size-dependent manner.
Spheroid growth is associated with an age-dependent accumulation of large endolysosomal vesicles, mechanically Pld3— A potential Alzheimer’s disease-associated risk gene encoding a lysosomal protein highly enriched in axonal spheroids.
Neuronal overexpression Pld3 leading to endolysosomal vesicle accumulation and spheroid expansion, exacerbating axonal conduction blockade. In contrast, Pld3 Deletion reduced the size of endolysosomal vesicles and spheroids and improved electrical conduction and neural network function.
Thus, targeted regulation of neuronal endolysosomal biogenesis could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independently of amyloid clearance.
