Swelling along brain’s axons may be true culprit in Alzheimer’s disease

Good news! I believe, this was one of the eye catching medical stories of this week! This is possibly a breakthrough!

"... 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 ... 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. ..."

From the 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."

Swelling along brain’s axons may be true culprit in Alzheimer’s disease | YaleNews Yale researchers have found that the disease’s debilitating symptoms may be the result of swelling caused by amyloid plaques in the brain.

PLD3 affects axonal spheroids and network defects in Alzheimer’s disease (open access)

Swelling surrounding amyloid plaques (light blue) in Alzheimer’s patients may be a culprit in dementia symptoms

Fig. 1: Plaque-associated axonal spheroids block AP propagation and disrupt interhemispheric connectivity.