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Researchers have identified a molecule that can effectively restore cognitive function and memory in mouse models of Alzheimer’s—a first for treatment strategies for the disease. In particular, the compound stimulates fast-firing neurons responsible for generating gamma oscillations, which are essential for memory and cognition.
For several decades, it has been widely accepted that the pathogenicity of Alzheimer’s disease comes in particular from the accumulation of beta-amyloid protein plaques in neurons (the “amyloid cascade” theory). Most therapeutic strategies, including drugs approved by the Food and Drug Administration (such as lecanemab and aducanumab), thus focus on the elimination of these plaques.
However, while this approach has been shown to slow disease progression, its ability to reverse cognitive impairment (which manifests as states of confusion that worsen over time) is significantly limited. They leave behind a brain that may be plaque-free, but not all the pathological alterations in the circuits and mechanisms of the neurons are corrected.
», explain Istvan Mody, professor of neurology and physiology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA Health).
On the other hand, drugs aimed at removing amyloid plaques usually have significant side effects. Clinical trials have shown that they can cause edema and sometimes fatal brain hemorrhages.
These findings have led to the exploration of new therapeutic approaches. In this vision, Mody and his colleagues propose a new compound that can reactivate the neuronal signals governing cognitive functions and memory. In other words, the molecule does not target amyloid plaques, but rather intervenes at the level of a biomolecular mechanism hitherto unexplored in the search for anti-Alzheimer’s treatments. There is really nothing like it on the market or experimentally that has been shown to be effective. ” says Mody.
A novel approach pharmacologically targeting gamma waves
To activate or suspend neuronal functions, the brain rhythmically emits electrical signals at different frequencies. Among these signals are gamma waves (30 to 120 Hz), which are part of the high-frequency oscillations. Generated by fast-firing interneurons containing parvalbumin (a calcium-binding protein), these oscillations govern the neural circuits underlying cognitive processes and working memory, the type of memory we use, for example, to remember a telephone number.
Studies have previously shown that in patients with early symptoms of Alzheimer’s, gamma oscillations were reduced even before amyloid plaques accumulate and impair cognitive functions. This effect has also been observed for other neurodevelopmental and neurological disorders such as Parkinson’s, depression, autism spectrum disorders (ASD), schizophrenia, epilepsy, etc.
To reduce Alzheimer’s symptoms, researchers have previously tried to use sound and visual stimulation at 40 Hz (the equivalent of the frequency of cats purring) to modulate gamma oscillations. However, although amyloid plaque levels were significantly reduced, the cognitive improvement achieved was limited.
As part of the new study, detailed in the journal
PNASMody and his team evaluated whether a pharmacological approach could be more effective. Indeed, by interacting with gamma-aminobutyric acid (GABA), certain receptors at the level of parvalbumin interneurons induce a reduction in gamma oscillations. GABA is the main inhibitory neurotransmitter of the central nervous system in mammals and birds, preventing prolonged activation of neurons.
The researchers developed the compound DDL-920 to inhibit these receptors, allowing interneurons to emit more powerful gamma oscillations. Our approach is unique because it aims to improve cognitive performance and working memory by engaging and amplifying endogenous gamma oscillations in the brain, enhancing the function of paravalbumin interneurons “, they explain in their document.
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