For decades, Alzheimer’s disease (AD) research has centered on one prevailing belief: beta-amyloid plaques are the primary cause of cognitive decline. These sticky, toxic protein clusters accumulate between neurons, supposedly blocking communication and triggering brain cell death. But despite efforts to clear these plaques, many clinical trials have shown little improvement in memory and thinking skills—posing a perplexing mystery for scientists.
Now, a groundbreaking study from researchers at the Federal University of Rio de Janeiro and the University of São Paulo is challenging this long-held dogma. Their surprising discovery reveals that hevin—a protein secreted by astrocytes, the brain’s supportive cells—can restore memory in mice experiencing age-related decline and Alzheimer’s, even without reducing amyloid plaque buildup.
This breakthrough shifts the Alzheimer’s treatment paradigm away from merely clearing harmful plaques toward actively restoring brain function. It opens an exciting new path for therapies that could bring hope to millions affected by this devastating disease.
Here’s the science behind the discovery—and why it could change everything.
What Is Hevin?
Hevin, also called SPARCL1 (SPARC-like protein 1), is a vital protein secreted mainly by astrocytes—the star-shaped support cells of the brain that nurture and maintain neurons. It plays a crucial role in synaptogenesis—the process of forming, stabilizing, and maturing synaptic connections, which are essential for neurons to communicate.
Initially studied for its role in brain development, hevin has now emerged as a key player in adult brain plasticity—the brain’s remarkable ability to adapt, rewire, and recover after injury or during learning.
Hevin acts like a biological “glue,” binding to adhesion molecules such as neurexins and neuroligins to bring neurons into alignment, facilitating efficient communication.
“Hevin is like a matchmaker for neurons,” explains Dr. Claudia da Silveira, co-author of the recent study. “It helps brain cells form stable, lasting connections—even in the challenging environment of an Alzheimer’s-affected brain.”
The Landmark Study: Restoring Memory Without Removing Plaques
Where the Study Was Conducted
This breakthrough research was led by neuroscientists at the Federal University of Rio de Janeiro (UFRJ) and the University of São Paulo (USP), two of Brazil’s premier research centers. Using genetic engineering, biochemical analysis, and advanced imaging, they investigated how increasing hevin levels in the brain influenced cognition and neural health in both aging and Alzheimer’s-model mice.
Their findings were published in 2023 in Nature Communications under the title:
“Astrocyte-secreted hevin rescues memory deficits in Alzheimer’s disease models without altering amyloid pathology.”
Experimental Design
Scientists used viral gene delivery to boost hevin expression specifically in the hippocampus—the brain’s memory center—in:
- Naturally aged mice experiencing memory decline
- Genetically modified mice that develop Alzheimer’s-like plaque buildup
They then assessed memory and learning through behavioral tasks like the Morris water maze and novel object recognition tests before and after treatment.
Key Findings
1. Memory Recovery Without Plaque Reduction
Surprisingly, even though beta-amyloid plaques remained untouched, mice treated with hevin showed remarkable improvements in memory. This overturns the long-held belief that clearing plaques is essential for cognitive recovery.
“This suggests cognitive decline is more closely linked to synaptic dysfunction than to plaque quantity,” says study lead Dr. Alexandre Takaki.
2. Strengthened Synapses
Microscopic examination revealed that treated mice had more numerous, thicker, and more mature dendritic spines—the tiny neuron structures where synapses form—indicating stronger, healthier neural connections.
3. Broad Molecular Impact
Mass spectrometry uncovered that hevin alters dozens of proteins related to neurotransmitter release, axon guidance, receptor clustering, and neural signaling—triggering a widespread molecular reset that boosts brain communication.
Why This Discovery Is Groundbreaking
Past Approaches: Targeting Plaques
For years, Alzheimer’s treatments focused on clearing beta-amyloid plaques using antibodies like:
- Aducanumab (Biogen)
- Lecanemab (Eisai)
- Donanemab (Eli Lilly)
Though effective at plaque reduction, these drugs yielded limited cognitive benefits and sometimes caused serious side effects, such as brain swelling (ARIA).
New Direction: Targeting Function, Not Debris
Hevin represents a paradigm shift: rather than removing pathological debris, it restores neural function by strengthening synaptic connections—offering a natural, astrocyte-driven pathway to revive memory.
Astrocytes: The Brain’s Unsung Heroes
While neurons have long been the focus, astrocytes—the most abundant glial cells—are now recognized as vital to brain health. They:
- Regulate neurotransmitters
- Maintain the blood-brain barrier
- Release growth factors like hevin
- Clear metabolic waste
- Shape synapse formation and pruning
“Astrocytes are not just support cells—they’re active architects of cognition,” says glial biologist Dr. Letícia Fernandes.
The hevin study highlights astrocytes as promising targets for treating neurodegenerative diseases.
Supporting Research
Previous studies have also linked hevin to synaptic health:
- Singh SK et al., Cell (2016): Showed hevin bridges neurexin-1α and neuroligin-1B to promote synapse formation.
- Risher WC et al., eLife (2014): Demonstrated astrocyte-secreted hevin’s role in developing excitatory synapses.
- Gan KJ & Südhof TC, eLife (2019): Revealed astrocyte signals selectively induce synapse formation in neuron subtypes.
These foundational works support the idea that boosting hevin can protect and restore neural connectivity—even in diseased brains.
Challenges and Next Steps
Though promising, this research is still early-stage. Key hurdles include:
- Human Translation: Mouse brains are simpler; whether hevin therapy works in humans remains unknown.
- Delivery: Hevin is a large protein; targeting it safely and effectively to specific brain regions is challenging.
- Gene Therapy Risks: Current viral delivery methods may cause immune responses or off-target effects.
- Long-Term Safety: Prolonged hevin increase might cause abnormal neural wiring or excitotoxicity.
Ongoing research is exploring:
- Small molecules that mimic hevin’s function
- CRISPR techniques to activate hevin genes
- Stem cell therapies to replenish astrocytes
Implications for Alzheimer’s Treatment
If successful in humans, hevin-based therapies could:
- Reverse early memory loss in mild cognitive impairment (MCI)
- Complement existing plaque-reducing drugs
- Reduce dependence on costly biologics
- Delay or prevent dementia onset
Most importantly, they could reshape Alzheimer’s research by shifting focus from clearing pathology to preserving and restoring brain function.
Final Thoughts: A New Frontier in Alzheimer’s Care
Discovering that hevin can restore memory in Alzheimer’s models without clearing plaques marks a monumental shift in understanding cognitive decline. It points to broken synaptic connections—not just toxic plaques—as the root cause.
By harnessing the brain’s own support system and enhancing neural communication, hevin opens a hopeful path toward healing—not just for Alzheimer’s patients, but for brain health in general.
As the field advances, one thing is clear: effective Alzheimer’s treatment must empower what remains functional—not just remove what’s damaged. And hevin may be the protein to lead 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.