Newly reported research led by BBRF grantees identifies a variety of changes in brain cells and synapses that are triggered to compensate for the gradual loss of neuronal functions during aging.

The study is noteworthy because it identifies a particular enzyme whose loss exacerbates memory impairment of the type seen in Alzheimer’s disease. The research also indicates that robust expression of the same enzyme is linked with cognitive resilience. One implication is that boosting this neuroprotective enzyme or processes associated with it could be a potential strategy to counteract aging-associated cognitive decline.

Amar Sahay, Ph.D., of Massachusetts General Hospital (MGH) and Harvard Medical School, recipient of a BBRF Independent Investigator grant in 2017 and BBRF Young Investigator grants in 2008 and 2006, heads a lab that is performing basic research dedicated to restoring cognition in brain disorders. The new paper he and colleagues have published in Nature Neuroscience fleshes out biomolecules and mechanisms relevant to the “cognitive reserve theory,” which posits that various compensatory mechanisms active during aging stave off cognitive decline and lower the risk for Alzheimer’s and other forms of age-related cognitive impairment.

The research team also included Cinzia Vicidomini, Ph.D., a 2017 BBRF Young Investigator, who is first author of the team’s paper, and Travis D. Goode, Ph.D., a 2020 BBRF Young Investigator. All are at MGH/Harvard.

It is generally accepted that healthy cognitive aging depends on a balance of vulnerability and resilience factors, whose actions dictate the tempo of emerging pathologies involved in the degradation of memory. Some of these factors include the loss of synapses, the tiny gaps across which neurons communicate; emergence in the brain of inflammation-promoting microglia (immune cells unique to the brain); dysregulation of fatty molecules called lipids; stress caused by excessive cellular oxidation; loss or decline of neurogenesis, the process in which new brain cells are generated in the adult hippocampus; and an imbalance between neural excitation and inhibition. Disruption of the balance among these many factors is thought to place the aging brain on a path of cognitive decline and increased risk for Alzheimer’s and other forms of cognitive impairment.

Implicit in cognitive reserve theory is the notion that pathological cognitive decline—including memory loss that greatly exceeds what occurs naturally as the brain ages—reflects a failure to compensate for the progressive increase in harmful biological changes over time. Studying this involves two objectives: to figure out how “compensatory” mechanisms naturally confer cognitive resilience; and to determine how these fail when pathological cognitive decline occurs. The new study contributes to our understanding of both.

Dr. Sahay and colleagues screened a particular population of cells in a part of the mouse hippocampus. This initial step reflected a great deal of knowledge already accumulated in prior research. This research has established that the hippocampus plays a crucial role in registering our experiences in the form of episodic memories—a type of long-term, explicit memory that allows us (and other mammals, including rodents) to recall specific events, individual experiences, and the exact contexts in which they happened.

A portion of the hippocampus of particular interest in the context of age-related memory decline is called the dentate gyrus (DG). The DG, among other things, contributes to memory formation by decreasing the interference of competing memories, often ones involving similar people, places, or things (a process called pattern separation). As the team notes in their paper, “dysfunction in the DG is considered a primary driver of aging-associated cognitive decline and a hallmark of mild cognitive impairment,” as well as a harbinger of disabling forms of cognitive decline such as Alzheimer’s.

In the initial step in their research, the screen the team conducted was designed to identify factors present in the DG that were induced by the loss of synapses. Such loss occurs in normal age-related memory loss as well as in Alzheimer’s and other pathological conditions. This screen drew the team’s attention to a particular cell type in the DG called dentate granule cells (DGCs). DGCs are directly involved in the pattern separation function of the DG, and are notable for being the cell type that is produced in adult hippocampal neurogenesis. Following synapse loss in the DG, the team found a significant increase in the expression of a particular enzyme in DGC cells. The enzyme, called Pla2g2f, is a phospholipase, involved in modifying lipids in cell membranes.

The team, by deleting the gene that encodes Pla2g2f in middle-aged mice, and thus preventing its expression in the DG during aging, observed a number of things that were likely related mechanistically: the exacerbation of aging-associated loss of synapses in the mice; the emergence of inflammatory microglia; the initiation of a process called reactive astrogliosis (in which cells called astrocytes are activated in response to injury or other pathology); disruption of lipids and the accumulation of “lipid droplets” (seen in aging brains with Alzheimer pathology); and, importantly, impairment of hippocampus-dependent memory formation.

When the team boosted Pla2g2f in DGC cells of aged mice, they found they could reverse this series of pathological impairments. They demonstrated that Pla2gf2 exerts its pro-resilience biological effects locally, affecting other cells in its midst, and also via long-range signaling in the living brain.

Hippocampus-dependent memory was preserved in the aged mice. Additional evidence of the protective role of Pla2g2f was found when expression of the enzyme was boosted in DGC cells of middle-aged animals: this, reported the team, prophylactically modified the trajectory of aging-associated cognitive decline.

Consistent with these findings, the team’s collaborators found that Pla2g2f expression was increased in the DG of aged cognitively resilient individuals even in the presence of Alzheimer’s disease-like pathology.

Yet another series of experiments involved the team’s use of stem cell technology to generate microglia and neurons, which were grown in culture dishes in the lab. Pla2g2f when expressed in human-derived neurons reduced lipid dysregulation and lipid droplet accumulation in microglia.

“We propose that numerous cellular and synaptic changes are triggered to compensate for gradual loss of neuronal functions during [normal] aging,” the team said, “and that potentiating [i.e., promoting] some of these changes may be sufficient to confer cognitive resilience.”

In summary, the researchers succeeded in identifying the Pla2g2f enzyme as an aging-sensitive compensatory neuroprotective factor “that counteracts cognitive decline” by maintaining normal lipid-modifying functions in the DG. Enhancing the cognitive resilience mechanism centered on the enzyme, they said, “may offer a novel therapeutic strategy to preserve the trajectory of healthy brain aging and reduce risk of mild cognitive impairments and late-onset Alzheimer’s disease.”