In the United States, women make up nearly two-thirds of all diagnosed cases of Alzheimer’s disease. On average, women live about 5 years longer than men, but that life expectancy discrepancy doesn’t likely account for such a large, sex-skewed prevalence for a disease that can take two decades to develop.
Neuroscientist Roberta Brinton at the University of Arizona’s Center for Innovation in Brain Science, in Tucson, suspects sex-linked biological factors—especially those connected to menopause, which brings a reduction in neuroprotective hormones—contribute to the disparity. But the mechanisms aren’t clearly understood. “If we can understand what happens in the aging female brain,” Brinton says, “then it could potentially tell us a lot about the disease itself.”
Working in rats, they recently offered further insights into the progression of some of these mechanisms in the Cell Press interdisciplinary journal iScience. Their typology could, they say, point to better inventions for Alzheimer’s patients.
An increasing body of evidence suggests that inflammation plays a critical role in Alzheimer’s progression, and some researchers hypothesize that misfolded proteins activate immune cells called microglia. Neuroinflammation has been observed in both men and women with Alzheimer’s, but along different trajectories.
Brinton’s lab sought to investigate. In rodent experiments led by neuroscientist Aarti Mishra, a scientific investigator in Brinton’s lab, researchers used RNA sequencing to examine the effects of aging on pathways of neuroinflammation in the hippocampus. The group identified three distinct phases of aging, each with its own neuroimmune profile.
During an “early chronological aging” phase, prior to the transition to menopause, the researchers found upregulated genes suggesting microglia reactivity and signaling molecules associated with the complement system, which among other things regulates synaptic pruning. “Pruning is good in development, but it’s not so good in an aging brain,” says Brinton. Previous studies on animal models of Alzheimer’s disease have similarly shown that activated microglia excessively prune synapses.
The researchers identified a second phase, characterized by endocrine aging, which marked the transition from peri-menopause to menopause as the animals went from regular cycling to irregular cycling. During this phase, their analysis showed genetic activity indicating an increase in the interferon response in the hippocampus and a decline in phagocytosis, the process by which microglia engulf and clear cellular debris. “It could be indicative of these microglia slowly losing their capacity to do their job,” Mishra speculates. They described a third phase that followed menopause (stable, low levels of estrogen) as “late chronological aging.” It was associated with an upregulation of MHC-II genes, which are also related to increased immune response and suggest another shift in reactivity among microglia in white matter tracts and the hippocampus.
However, follow-up experiments revealed a way to subvert that progression. When the researchers administered estradiol—the major form of mammalian estrogen—to rats immediately after surgical removal of the ovaries, it suppressed genes in the interferon and complement system, thereby preventing the development of the neuroinflammatory profile associated with late chronological and endocrinological aging. In animals that received estradiol two weeks after ovary removal, however, only a few of the genes associated with an interferon response were suppressed.
The researchers then used an existing dataset of human hippocampal gene expression to look for the same patterns among women in the three distinct phases of aging. They also compared the data to age-matched expression profiles from men. The microglial activity genes that changed during the three phases in the animal groups showed similar changes in regulation within the human data.
The findings suggest that neurodegenerative conditions may begin during a preclinical phase—possibly even before the transition to menopause—and hint at a disease development phase that hasn’t been explored, says Brinton. But maybe that’s not surprising: The disease takes about 20 years to develop, and most women with Alzheimer’s are diagnosed about 20 years after menopause.
The new analysis clearly lays out the correlation between ages and pathways of neuroinflammation in the female animal model, says neurologist Oleg Butovsky at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts. These could be useful in knowing where and when to intervene for therapeutics. “The study highlights the importance of sex/gender, the estrogen pathways, and microglia,” he notes, while adding that the work doesn’t necessarily introduce a new concept and generally supports what researchers already knew.
But Brinton, senior author on the new work, believes that the research can help scientists identify strategies not only for how to intervene and prevent neurodegenerative diseases, but also for when to intervene. “It suggests we can have a precision neuroimmune therapy that targets this early phase, to this innate immune system,” she says.
Now in follow-up work, the researchers are looking for blood biomarkers that correlate to the neuroinflammatory changes her work identified in the brain. Such a marker, says Brinton, may help clinicians and researchers determine when a disease is in its earliest—and possibly most treatable—stage.
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