Researchers discover molecule that reverses cognitive deficits associated with dementia and aging

Dementia affects millions globally, impacting memory, reasoning, and everyday activities. As the population ages, understanding and addressing cognitive decline becomes increasingly critical.

Alzheimer's disease, the most common form of dementia, affects around 50 million people worldwide. This number is projected to triple to over 150 million by 2050, especially burdening low-income and middle-income countries. Globally, dementia care costs nearly $1 trillion annually.

Yet, despite extensive research, effective treatments for dementia remain limited. Alzheimer's disease is traditionally linked with amyloid-beta plaques and neurofibrillary tangles of tau proteins, believed to disrupt brain function. But recent findings suggest that the soluble forms of these proteins, rather than solid plaques, might play a greater role in impairing synapses—the critical connections between neurons.

Astrocytes, star-shaped brain cells, maintain the health of neurons by supporting synaptic connections. They help form, maintain, and prune synapses, directly influencing cognitive functions. Scientists have recently shifted focus from neurons to astrocytes, exploring their potential for protecting the brain from damage and decline.

One key astrocyte protein, Hevin, also known as SPARC-like1, has attracted attention due to its role in strengthening synapses. Hevin helps bridge connections between neurons, crucial for learning and memory. Its counterpart, SPARC, typically works against Hevin's actions, reducing synapse formation. In Alzheimer's brains, SPARC appears abundant, while Hevin decreases, suggesting an imbalance might accelerate cognitive decline.

Scientists from Brazil’s Federal University of Rio de Janeiro (UFRJ) and the University of São Paulo (USP) explored how boosting Hevin levels in astrocytes could influence aging brains and Alzheimer's disease. The study, recently published in Aging Cell, tested the effects of Hevin in mice genetically engineered to mimic Alzheimer’s and in healthy aging mice.

The researchers used viral vectors to enhance Hevin specifically within astrocytes of the hippocampus, the brain region essential for memory. Flávia Alcantara Gomes, head of Cellular Neurobiology at UFRJ, explained, “We found that the overproduction of Hevin reverses cognitive deficits in aged animals by improving synaptic quality.”

Remarkably, mice with increased Hevin showed improved cognitive abilities in memory and learning tasks. They navigated mazes and completed memory tests more effectively than untreated animals. These improvements came with clearer, stronger synapses, indicating that Hevin had indeed strengthened neural connections.

Interestingly, increased Hevin did not reduce amyloid plaques, traditionally linked to Alzheimer's severity. Felipe Cabral-Miranda, lead author and biomedical scientist at UFRJ, noted, “Although cognitive deficits improved significantly, plaque levels remained unchanged. This highlights Alzheimer's complexity and suggests plaques alone may not be sufficient to cause the disease.”

This unexpected finding supports a growing belief among scientists that amyloid plaques may be symptoms rather than primary causes of Alzheimer's. Cognitive decline appears more closely related to how effectively neurons communicate rather than simply plaque presence.

Researchers also examined how Hevin influenced brain proteins using advanced proteomics at USP's Redoxoma laboratory. Proteomics identifies proteins expressed in cells, revealing clues about how cellular processes change with disease or treatment. The results showed 89 proteins were altered by increased Hevin, specifically proteins involved in synapse function.

Danilo Bilches Medinas from USP explained, “Synapses rely heavily on proteins for neuronal signaling. Proteomics revealed that boosting Hevin regulated several protein groups critical for synaptic strength, enhancing neuron-to-neuron connections and boosting cognitive performance.”

These findings suggest that targeting astrocytes, rather than neurons alone, could lead to innovative treatments for dementia and age-related cognitive decline. By focusing on proteins like Hevin, scientists open doors to novel therapeutic approaches beyond traditional drug targets.

Despite these promising results, researchers emphasize caution. Current findings come from animal models, and translating them into human therapies presents significant hurdles. One critical issue is the blood-brain barrier, a protective layer preventing many molecules from entering the brain. Future drugs must overcome this barrier without losing effectiveness.

Gomes emphasized, “In the future, drugs replicating Hevin's effects might be developed. However, today’s main achievement is better understanding Alzheimer's molecular mechanisms. By shifting attention to astrocytes, we’ve identified new potential strategies for addressing cognitive impairment.”

Cabral-Miranda agreed, stressing the significance of these results as "proof of concept." He added, “Our findings reinforce that Alzheimer's is multifaceted. Addressing synaptic health directly through astrocytes could revolutionize how we treat cognitive decline.”

This groundbreaking work marks a significant step forward in Alzheimer's research, highlighting astrocytes and their proteins as critical players. Future studies will aim to determine if similar effects occur in humans and how effectively potential drugs based on Hevin can cross into the human brain.

As Alzheimer's continues to burden individuals, families, and societies, research like this provides hope for more effective and targeted treatments. By broadening scientific focus beyond traditional amyloid-targeting therapies, new solutions emerge, offering brighter prospects for aging populations worldwide.

Note: The article above provided above by The Brighter Side of News.

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