Immune cell activity in the brain differs between males and females in ways that may explain why some neurodegenerative diseases affect the sexes differently, according to a new study from Weill Cornell Medicine scientists.

Dr. Li Gan, the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, is senior author of “Microglial MicroRNAs Mediate Sex-Specific Responses to Tau Pathology,” which published Dec. 23 in Nature Neuroscience.

The study compared brain-resident immune cells called microglia in male and female mice. Microglia in Alzheimer’s disease and other neurodegenerative disorders appear to help protect the brain from the disease process, including the abnormal clumps of protein that accumulate in these disorders, but also may harm neurons and worsen disease through excess inflammatory activity.

The scientists showed that male and female mouse microglia differ in the sets of molecules that normally regulate their gene activity and in their responses to deposits of tau protein, a feature of several neurodegenerative disorders, including Alzheimer’s.

“We hope that by studying these pronounced sex differences, we’ll get a better understanding of the roles of microglia in neurodegenerative disease, as well as clues to new therapeutic strategies,” said Gan, also director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine.

Some studies suggest that men and women may differ in their susceptibilities to neurodegeneration. For example, women with Alzheimer’s disease appear to experience a faster disease course; one recent study found that aggregated tau protein, a broad marker of Alzheimer’s disease progress, spreads more rapidly in the brains of women with Alzheimer’s than with those of men.

These sex differences may arise in part from differences in the brain’s response to neurodegenerative disease processes. One clue is that microglia in male and female mice differ in their gene activity, especially with aging.

In their study, Gan and colleagues looked “under the hood” of microglia at molecules called micro-RNAs (miRNAs) that are extensively involved in regulating these cells’ activities. The researchers found that even in healthy lab mice, the sets of miRNAs that are active in microglia differ greatly between males and females.

And when the researchers made a genetic alteration that essentially removed all miRNAs from microglia, thereby removing their normal regulatory influence on gene activity, the resulting changes in gene activity were far greater in the male microglia.

Gan and her team found similar differences between male and female microglia in a commonly used mouse model of tau neurodegeneration: The cells differed greatly in their gene activity at baseline and the changes were far greater in male microglia after their miRNAs were removed. Removal of miRNAs also led to the development of a more inflammatory state in male microglia as well as worsened tau pathology in the brains of the male mice.

“These findings show that there are sex-specific differences in microglial miRNAs, which may in turn contribute to sex differences observed in neurodegenerative diseases,” said Gan, also a professor of neuroscience in the Feil Family Brain and Mind Research Institute.

Lay Kodama and Joe C. Udeochu, members of the Gan lab at Weill Cornell Medicine, also contributed to this work, as did researchers from the University of California, San Francisco; the University of California, Santa Barbara; the Gladstone Institute of Neurological Disease in San Francisco; Stanford University School of Medicine; and Virginia Polytechnic Institute.

This work was supported in part by grants from the National Institutes of Health.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.