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Unlocking mystery of memory formation opens door to Alzheimer’s treatment

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Unlocking mystery of memory formation opens door to Alzheimer’s treatment

For the first time, researchers have identified how the brain’s fatty acids and the genes that control them are crucial to memory formation. In addition to increasing our understanding of how memories are formed, the discovery opens the door to novel treatments for memory-affecting diseases such as Alzheimer’s.

The human brain is highly enriched with fatty compounds called lipids, which comprise around 60% of its weight. A type of brain lipid, phospholipids, and their free fatty acid (FFA) building blocks comprise neuronal membranes that play a crucial role in learning and memory. However, the mechanisms by which neuronal activity affects the brain’s lipid landscape and subsequent memory formation are poorly understood.

Now, a new study led by researchers at the University of Queensland (UQ), in collaboration with the Universities of New South Wales, Strasbourg, and Bordeaux, The Scripps Research Institute and the Baylor College of Medicine, has shed light on the molecular mechanisms and genes underlying the creation of memories.

“We’ve shown previously that levels of saturated fatty acids increase in the brain during neuronal communication, but we didn’t know what was causing these changes,” said Isaac Akefe, the study’s lead author. “Now, for the first time, we’ve identified alterations in the brain’s fatty acid landscape when the neurons encode a memory.”

During neurological processes, the enzyme phospholipase A1 (PLA1) hydrolyzes phospholipids to produce saturated FFAs, changing the local brain environment. Studies have shown that phospholipids such as PLA1 and their FFA metabolites bind to key proteins such as syntaxin-1A (STX1A) and Munc18-1 (STXBP1) to regulate synaptic vesicles that release neurotransmitters and are essential for propagating nerve impulses between neurons. The importance of PLA1 to neuronal function is demonstrated by the genetic disorder hereditary spastic paraplegia (HSP), where a mutation in the DDHD2 gene that encodes PLA1 is associated with cognitive dysfunction.

To investigate the role of DDHD2 in memory formation, the researchers used a DDHD2 knockout mouse model of HSP and tracked the animals’ neuromotor and cognitive decline throughout their lifespan. They assessed changes to 19 FFAs across five brain regions in response to a procedure that tested reward-based associative memory. While the testing procedure drove region-specific changes in the brain’s lipid landscape in control mice, characterized by an increase in saturated FFAs, DDHD2 knockout mice exhibited a significant reduction in saturated FFA response, even before memory impairment occurred.

“Human mutations in the PLA1 and the STXBP1 genes reduce free fatty acid levels and promote neurological disorders,” said Frederic Meunier, one of the study’s corresponding authors. “To determine the importance of free fatty acids in memory formation, we used mouse models where the PLA1 gene is removed. We tracked the onset and progression of neurological and cognitive decline throughout their lives. We saw that even before their memories became impaired, their saturated free fatty acid levels were significantly lower than control mice. This indicates that this PLA1 enzyme, and the fatty acids it releases, play a key role in memory acquisition.”

The findings have important implications for understanding how memories are formed and developing treatments for memory-affecting diseases.

“Our findings indicate that manipulating this memory acquisition pathway has exciting potential as a treatment for neurodegenerative diseases, such as Alzheimer’s,” Meunier said.

The study was published in The EMBO Journal.

Source: University of Queensland

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