Could this natural protein be the key to reversing age-related memory loss?

A new study published in Aging Cell has identified a promising molecule that may help reverse cognitive decline associated with both normal aging and Alzheimer’s disease. Scientists found that increasing the levels of a protein called Hevin—secreted by astrocytes, a type of support cell in the brain—improved memory and learning in middle-aged mice. The intervention worked in both healthy animals and those genetically modified to model Alzheimer’s disease, and it did so without affecting the buildup of amyloid plaques, a hallmark of the condition.

The researchers, based at the Federal University of Rio de Janeiro and the University of São Paulo in Brazil, were motivated by growing evidence that astrocytes play an underappreciated role in brain health. Historically, Alzheimer’s research has focused heavily on neurons and the accumulation of amyloid beta plaques. But in recent years, studies have shown that astrocytes help regulate synapse formation and stability, and their dysfunction may contribute to cognitive impairment. This research aimed to explore how one astrocyte-secreted protein, Hevin, might influence the aging brain.

“I have dedicated most of my life to studying how the brain works at the molecular level, which drove me to question: what happens there as we get older that impacts its normal function? That question dictates most of my projects today,” said study author Felipe Cabral-Miranda, a staff scientist at the Federal University of Rio de Janeiro.

To test this, the researchers examined Hevin expression in brain tissue from both Alzheimer’s patients and healthy controls. They found that Hevin levels were significantly lower in the brains of people with Alzheimer’s, particularly within astrocyte subtypes linked to the disease. These findings were mirrored in a mouse model of Alzheimer’s known as APP/PSEN, which shows memory loss and plaque accumulation. In both humans and mice, Hevin appeared to be reduced in areas of the brain important for memory.

Building on this observation, the researchers designed an experiment to increase Hevin production specifically in the hippocampal astrocytes of mice. They used a type of viral vector—adeno-associated virus (AAV)—to deliver the gene for Hevin under a promoter that activates only in astrocytes. The gene was injected directly into the hippocampus, the brain region critical for memory. This was done in both wild-type mice and the APP/PSEN Alzheimer’s model mice at middle age.

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After either one or six months of Hevin overexpression, the mice underwent a battery of behavioral tests designed to assess different forms of memory. These included the novel object recognition test, the Barnes maze for spatial learning, and the novel object location task. In all cases, mice with elevated astrocytic Hevin levels performed significantly better than controls. They were better at remembering object placements and navigating to specific locations, and they showed more engagement with new stimuli.

“Initially, we tested if an artificial genetic manipulation in the brain could prevent the negative features in Alzheimer’s disease using an animal model,” Cabral-Miranda told PsyPost. “To our surprise, those interventions could also benefit aged animals without Alzheimer’s disease! In other words, we found a molecule target that could impact both pathological and also normal brain aging in mammals.”

These cognitive improvements occurred even though the amyloid plaque burden in the brains of the Alzheimer’s model mice remained unchanged. Using immunofluorescence imaging, the researchers confirmed that Hevin did not reduce the number or size of beta-amyloid plaques. This suggests that the improved cognition came from other mechanisms, most likely involving synaptic structure and function.

“We found that our treatment ameliorated age-associated cognitive decline but did not impact the appearance of beta-amyloid plaques, which are one of the ‘hallmarks’ of Alzheimer’s disease
and is believed to be one of its primary causes,” Cabral-Miranda said. “Our data indicate that we can improve cognitive decay in the disease by alternative mechanisms.”

To understand those mechanisms, the team conducted a proteomic analysis of the hippocampus in treated and untreated mice. They found that Hevin overexpression altered the levels of numerous proteins involved in synaptic signaling, dendritic development, and cytoskeletal dynamics. In Alzheimer’s model mice, Hevin increased the expression of proteins related to chemical synapse modulation, such as Shank3, Cask, and Ntrk2—key players in maintaining and stabilizing synapses. In wild-type mice, the affected proteins were more involved in actin filament organization and neurotransmitter release.

Confocal microscopy revealed increased colocalization of presynaptic and postsynaptic proteins in the hippocampus of mice with elevated Hevin. This suggests stronger or more mature synapses, which aligns with the observed behavioral improvements. Interestingly, the sets of proteins influenced by Hevin differed between the Alzheimer’s model and the wild-type mice, implying that the protein exerts its beneficial effects through different biological pathways depending on the brain’s condition.

To assess whether these findings have relevance for humans, the researchers analyzed gene expression data from Alzheimer’s patients and found that Hevin levels in brain tissue correlated positively with the expression of several key synaptic genes. This reinforces the idea that Hevin supports healthy brain function by regulating synaptic components.

The study introduces Hevin as a promising candidate for therapies targeting cognitive decline. Because Hevin is secreted by astrocytes and can influence neurons indirectly, it may be possible to develop drugs that stimulate its production or mimic its effects. One of the challenges will be designing compounds that can cross the blood-brain barrier and maintain Hevin’s beneficial actions without unwanted side effects.

The findings provide evidence that “it is possible to ameliorate some aspects of brain aging pharmacologically and in the near future we will be able to delay cognitive decay using those strategies,” Cabral-Miranda told PsyPost.

“Hevin is a well-known molecule involved in neural plasticity. It’s naturally secreted by cells in the central nervous system that support the functioning of neurons and are known as astrocytes. We found that the overproduction of hevin is capable of reversing cognitive deficits in aged animals by improving the quality of synapses in these rodents,” added Flávia Alcantara Gomes, the head of the Cellular Neurobiology Laboratory the Institute of Biomedical Sciences.

But the researchers emphasize that this is early-stage work in mice, and there is a long road ahead before any human applications become available. Still, their findings challenge the dominant narrative that reducing amyloid plaques is the key to reversing Alzheimer’s symptoms. Instead, their work highlights the potential of glial-targeted therapies and a broader approach to treating age-related cognitive decline.

Some limitations of the study include its reliance on animal models and invasive gene delivery techniques. While the APP/PSEN mouse model captures several aspects of Alzheimer’s disease, it does not replicate the full complexity of the human condition. Moreover, the AAV method used to increase Hevin is not yet practical for clinical use. Future research will need to explore whether Hevin-based therapies can be delivered systemically, whether Hevin levels in the blood or cerebrospinal fluid could serve as biomarkers for cognitive decline, and how the molecule behaves across different stages of aging and neurodegeneration.

“We performed an analysis that showed that the molecules impacted by our treatment were also observed in human brain samples, which indicates that it is strongly associated with human brain cognitive decline as well,” Cabral-Miranda noted. “However, it is important to highlight that our preclinical data arises from animal models (mice) and further studies must be performed using human cohorts to confirm them. It is also important to highlight that the molecule Hevin is a bit hard to be converted in an efficient drug, although our study indicated a path to generate more efficient drugs for dementia.”

The researchers are currently investigating whether Hevin levels change in the blood of older adults and whether such changes might help predict cognitive decline or Alzheimer’s disease. They also hope to understand how astrocytes differ across brain regions and how this diversity affects synaptic health.

“We aim to study if the levels of this molecule are changed in the blood of aged individuals as a means to determine if it can be used as a more accurate test for Alzheimer’s and other forms of dementia,” Cabral-Miranda said.

“Of course, in the future it’ll be possible to develop drugs that have the same effect as hevin. For now, however, the fundamental benefit of this work is a deeper understanding of the cellular and molecular mechanisms of Alzheimer’s disease and the aging process. The originality lies in understanding the role of the astrocyte in this process. We’ve taken the focus away from neurons, shedding light on the role of astrocytes, which we’ve shown could also be a target for new treatment strategies for Alzheimer’s disease and cognitive impairment,” Gomes said.

The study, “Astrocytic Hevin/SPARCL-1 Regulates Cognitive Decline in Pathological and Normal Brain Aging,” was authored by Felipe Cabral-Miranda, Ana Paula Bergamo Araujo, Danilo Bilches Medinas, and Flávia Carvalho Alcantara Gomes.