Yale research may uncover the true cause of Alzheimer's — Swelling of brain axons

As stated in the release, Yale scientists found that these swellings accumulate in lysosomes, claiming that as the swelling grows, it blunts the transmission of normal electrical signals from one area of the brain to another. According to the researchers, this buildup of lysosomes results in swelling along axons, which sets off dementia's devastating effects.

“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, 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.

A dramatic reduction of axonal swelling

The scientists also found that lysosomes contain a protein called PLD3 that made these organelles expand and clump together along axons, ultimately causing axon enlargement and the breakdown of electrical conduction.

In mice with a condition similar to Alzheimer's disease, they discovered that removing PLD3 from neurons using gene therapy significantly decreased axonal swelling. 

PLD3 could be employed as a marker in identifying the risk of Alzheimer's disease, and as a target for future therapeutics also Yale scientists herald.

“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.

More about axons

In vertebrates, an axon, also known as a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that normally transports electrical impulses known as action potentials away from the nerve cell body. The axon's role is to transmit information to various neurons, muscles, and glands. The axons of specific sensory neurons (pseudounipolar neurons), such as those for touch and temperature, are called afferent nerve fibers. The electrical impulse travels down them from the periphery to the cell body and along another branch of the same axon to the spinal cord.

Many inherited and acquired neurological illnesses that affect both peripheral and central neurons might be caused by axon malfunction.

Study abstract:

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.