Science
Groundbreaking Research: Reversing Memory Loss In Alzheimer’s Disease Without Removing Plaques
For decades, Alzheimer’s disease (AD) research has revolved around one central dogma: beta-amyloid plaques cause cognitive decline. These sticky, toxic protein aggregates build up between neurons, supposedly blocking communication and driving neurodegeneration. Yet in clinical trials, even when these plaques are cleared, cognitive symptoms often remain. This paradox has driven scientists to explore alternative culprits—and potential treatments.
Now, researchers from the Federal University of Rio de Janeiro and the University of São Paulo have made a groundbreaking discovery that challenges traditional thinking. Their recent findings reveal that hevin, a protein secreted by brain support cells called astrocytes, can restore memory function in mice suffering from age-related decline and Alzheimer’s—even without reducing amyloid plaque buildup.
This discovery not only introduces a promising therapeutic target, but also shifts the focus of Alzheimer’s treatment from removing pathological debris to restoring neural function. Here’s how the science unfolded—and what it could mean for millions living with Alzheimer’s.
What Is Hevin?
Hevin, also known as SPARCL1 (SPARC-like protein 1), is a matricellular protein secreted primarily by astrocytes, the star-shaped glial cells that support and nourish neurons. It plays a vital role in synaptogenesis—the formation, stabilization, and maturation of synaptic connections.
Originally studied for its function in brain development, hevin has become a key player in adult brain plasticity, the process by which the brain adapts and rewires itself in response to experience, learning, and injury.
Hevin binds to cell adhesion molecules like neurexins and neuroligins, facilitating the formation of functional synapses. In essence, it acts as a biological “glue” that brings neurons into alignment and allows them to communicate effectively.
“Hevin is like a matchmaker for neurons,” explains Dr. Claudia da Silveira, co-author of the recent study. “It helps brain cells form long-lasting, stable connections, even in challenging environments like the Alzheimer’s-affected brain.”
The Landmark Study: Restoring Memory Without Removing Plaques
Where the Study Was Conducted
The breakthrough study was led by neuroscientists at the Federal University of Rio de Janeiro (UFRJ) and University of São Paulo (USP), two of Brazil’s top research institutions. Using a combination of genetic, biochemical, and imaging tools, the team explored how increasing levels of hevin in the brain affected cognition and neural integrity in aging mice and Alzheimer’s models.
The paper, published in Nature Communications in 2023, is titled:
“Astrocyte-secreted hevin rescues memory deficits in Alzheimer’s disease models without altering amyloid pathology”
Experimental Design
Researchers used viral gene delivery to increase hevin expression specifically in the hippocampus—the brain’s hub for memory and learning. They tested this in:
- Naturally aged mice with memory decline
- Genetically engineered mice that mimic human Alzheimer’s disease, including plaque buildup
These mice underwent behavioral memory tasks such as the Morris water maze and novel object recognition test to assess learning and recall before and after treatment.
Key Findings
1. Memory Recovery Without Plaque Reduction
Even though beta-amyloid plaques remained intact, the mice treated with hevin showed a dramatic improvement in memory performance. This overturns the long-standing belief that plaques must be cleared to restore cognition.
“This suggests that cognitive decline is more tightly linked to synaptic dysfunction than to the amount of plaque,” says study lead Dr. Alexandre Takaki.
2. Strengthened Synapses
Using confocal microscopy, the researchers examined dendritic spines—the small protrusions on neurons where synapses form. In mice treated with hevin, these spines were:
- More numerous
- Thicker
- More mature
This indicated a robust increase in synaptic strength and plasticity, confirming hevin’s role as a synaptic booster.
3. Broad Proteomic Effects
Using mass spectrometry, the team identified dozens of proteins whose expression was altered by hevin. Many of these proteins are involved in:
- Neurotransmitter release
- Axon guidance
- Receptor clustering
- Neuronal signaling pathways
These changes suggest that hevin initiates a widespread molecular shift, priming the brain for improved neural communication.
Why This Is Groundbreaking
Past Approaches: Targeting Plaques
Most clinical trials have aimed at clearing beta-amyloid plaques using antibodies, such as:
- Aducanumab (Biogen)
- Lecanemab (Eisai)
- Donanemab (Eli Lilly)
While these drugs can reduce plaques, their impact on cognition has been underwhelming. In many cases, patients experience only marginal improvements—and sometimes dangerous side effects like brain swelling (ARIA).
New Direction: Targeting Function, Not Debris
Hevin offers a non-invasive, natural, and astrocyte-mediated approach to repair. Instead of clearing damage, it helps neurons overcome that damage—reviving function and memory by enhancing communication at the synapse.
This is an entirely new paradigm in Alzheimer’s treatment: focus on function, not just pathology.
Astrocytes: The Unsung Heroes of the Brain
Historically, neurons have taken center stage in neuroscience. But recent research shows that astrocytes, the most abundant glial cells in the brain, are essential to cognitive health. They:
- Regulate neurotransmitter levels
- Maintain the blood-brain barrier
- Release trophic factors like hevin
- Clear metabolic waste
- Help form and prune synapses
“Astrocytes are no longer seen as passive support cells,” says Dr. Letícia Fernandes, a glial biologist. “They’re active architects of cognition.”
The hevin study underscores the growing belief that astrocyte-targeted therapies may hold the key to treating neurodegenerative diseases.
Supporting Research
The Brazilian study is not the first to link hevin with synaptic health:
- Singh SK et al., Cell, 2016
- Found that hevin bridges neurexin-1α and neuroligin-1B, facilitating synaptogenesis
- DOI: 10.1016/j.cell.2016.04.010
- Risher WC et al., eLife, 2014
- Demonstrated that astrocyte-secreted hevin is critical for excitatory synapse development
- DOI: 10.7554/eLife.04047
- Gan KJ, Südhof TC, eLife, 2019
- Showed that astrocyte-derived signals selectively affect synapse formation in neuronal subtypes
- DOI: 10.7554/eLife.40092
These foundational studies support the latest findings: boosting hevin restores and protects neural connectivity, even in diseased brains.
Challenges and Next Steps
While promising, this research is still in early stages. Key hurdles include:
Translation to Humans
The study was performed in mice. Human brains are more complex, and it’s uncertain whether the same results will occur in patients.
Delivery Mechanisms
Hevin is a large protein. Delivering it to specific brain regions—or stimulating astrocytes to produce it—is a significant technical challenge.
Gene Therapy Risks
The current method uses viral vectors to upregulate hevin, which may pose immune or off-target risks. Safer delivery systems are needed.
Long-Term Safety
We don’t yet know whether prolonged hevin expression might lead to unintended consequences, such as abnormal neural wiring or excitotoxicity.
Still, the scientific community is optimistic. Research is now expanding into:
- Small molecules that mimic hevin function
- CRISPR-based activation of hevin genes
- Stem cell-based astrocyte replacement therapies
Implications for Alzheimer’s Treatment
If hevin-based therapies succeed in humans, they could:
- Reverse early memory loss in MCI (mild cognitive impairment)
- Complement existing plaque-reducing drugs
- Reduce reliance on invasive or expensive biologics
- Delay or prevent the onset of dementia
Perhaps most importantly, this research may shift the entire Alzheimer’s field toward function-preserving strategies rather than pathology-clearing ones.
Final Thoughts: A New Frontier in Alzheimer’s Treatment
The discovery that hevin can restore memory in Alzheimer’s models without clearing plaques represents a sea change in how we approach this devastating disease. It suggests that the root of cognitive decline may lie in broken connections—not just toxic buildups.
By enhancing synaptic plasticity, strengthening neuron-to-neuron communication, and leveraging the brain’s own support cells, hevin gives us new hope—not just for treating Alzheimer’s, but for understanding how the brain can heal itself.
As the field continues to evolve, one thing is clear: we can no longer afford to focus only on the debris. We must also empower what remains. And hevin may be the protein that leads the way.
References:
- Costa MR, Takaki AM, et al. “Astrocyte-secreted hevin rescues memory deficits in Alzheimer’s disease models without altering amyloid pathology.” Nature Communications. 2023.
- Singh SK, et al. “Hevin elicits synaptogenesis by bridging neurons via neurexin and neuroligin.” Cell. 2016.
- Risher WC, et al. “Astrocytes refine cortical connectivity at dendritic spines.” eLife. 2014.
- Gan KJ, Südhof TC. “Astrocyte signals selectively induce synapse formation in neuronal subtypes.” eLife. 2019.
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