Molecular Mechanism Responsible for Synapse Loss in Alzheimer’s Disease Revealed

Molecular Mechanism Responsible for Synapse Loss in Alzheimer’s Disease Revealed

Researchers from the UNSW School of Biotechnology and Biomolecular Sciences and School of Medical Sciences and the Neuroscience Research Australia have uncovered a new molecular mechanism responsible for the loss of synapses, a key event in the early pathogenesis of Alzheimer’s disease. The research paper, entitled “Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease,” was published in Nature Communications.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of extracellular deposits of amyloid protein and early loss of synapses, an event seen as crucial in the loss of memory and cognitive impairment that are characteristic of the disease. Synapses are structures that allow communication through electrical and chemical signals between nerve cells and are therefore essential to proper neuronal function, thought, speech, voluntary and involuntary actions. The integrity and development of synaptic structures and contacts is maintained by cell adhesion molecules, responsible for connecting synaptic membranes and regulating their plasticity in the adult brain.

The research team led by Dr. Vladimir Sytnyk studied one of these proteins, the neural cell adhesion molecule 2 (NCAM2). Through analysis of post-mortem brain tissues from AD patients and healthy controls, the researchers found this protein to be enriched in the synapses of healthy hippocampus, while the levels of NCAM2 were significantly reduced in hippocampal synapses in AD brain tissues. Using a mouse model, the scientists also showed that beta-amyloid (Aβ), the main component of plaques characteristic of AD, directly interacts with NCAM2 in vivo, leading to its breakdown and inducing synaptic loss. Researchers further theorize that the damaging effects of cleaved extracellular NCAM2 on synapses may further worsen Aβ toxicity in the pathogenesis of AD. This mechanism explains why the protein NCAM2 is changed in the hippocampus synapses in AD brains, though researchers state that the molecular mechanisms responsible for the beta-amyloid effect on NCAM2 and the real importance of these events on the pathogenesis of AD remain to be determined.

Dr. Vladimir Sytnyk explained in a press release, “Our research shows the loss of synapses is linked to the loss of NCAM2 as a result of the toxic effects of beta-amyloid. It opens up a new avenue for research on possible treatments that can prevent the destruction of NCAM2 in the brain.”

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