ALZHEIMER: Discovery of the first biomarkers

Studies in a mouse model of the disease show that increased activity of these proteins leads to seizures associated with early stages of neurodegeneration, and that inhibition of the same proteins slows the onset and progression of the disease. Results that have yet to be confirmed in humans.

Neuronal specific protein PSD-95, a new marker and a new target?

Lead author Nien-Pei Tsai, a professor of molecular and integrative physiology at the University of Illinois, highlights the promise of earlier diagnosis and more effective treatment of the disease. His team is working on mouse models that produce more beta-amyloid protein, which gradually aggregates in Alzheimer’s disease, forming plaques in the brain that interfere with neuronal activity.

Studying focused for the first time on a much earlier period in the life of these mouse models of Alzheimer’s disease. The goal is to be able to detect pathogenesis as early as possible in order to identify new early markers and try to slow their progression.

“We know that Alzheimer’s disease is irreversible. But if we can slow the progression or even delay the onset of the disease, we can improve or maintain patients’ quality of life.”

Observation of early neuronal development, first in neuronal cultures (in vitro) and then in these mouse models shows:

• an increase in the level of the PSD-95 protein, the function of which is to attract other receptors to the synaptic surface, where 2 neurons communicate and transmit signals to each other;
• These high levels of PSD-95 promote brain hyperexcitability, a common phenotype in the early stages of Alzheimer’s disease: this phase of hyperexcitability, or high susceptibility to seizures, in the brain precedes neurodegeneration;
• Increased PSD-95 has been confirmed as a factor in epilepsy-like activity because when researchers suppress PSD-95, receptor activity at the synapse decreases, which also causes seizures and mortality.

Taken together, these results indicate that

PSD-95 protein promotes hyperexcitability in the early stages of Alzheimer’s disease.

PSD-95 appears here as an early biomarker for the development of Alzheimer’s disease and high susceptibility to seizures. Moreover, anti-PSD-95 antibody inhibitors may show promise already in the early stages of Alzheimer’s disease.

Many more preclinical studies and clinical trials are still needed to confirm these results, and studies are also underway on other receptors on the synaptic surface that PSD-95 interacts with.

Among them is the NMDA receptor, which contributes to the death of nerve cells in Alzheimer’s disease. Inhibition of PSD-95 may also inhibit NMDA and slow down cell death.