The developmental effects of sex chromosomes and hormones specify microglial inflammation in Alzheimer's diseaes

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Principal Investigator: ERIN G REED
Organization: NORTHEAST OHIO MEDICAL UNIVERSITY
Fiscal Year: 2024
Award: $390,000
Funding agency: National Institute on Aging

PROJECT SUMMARY/ABSTRACT
 Although women are known to be disproportionally affected by Alzheimer’s disease (AD), the
underlying biology for this difference is unresolved. Our long-term goal is to help develop therapies that can be
used in the prevention and treatment of Alzheimer’s disease and other dementias where inflammation plays a
critical role. The overall objectives in this application are to (i) define the mechanisms that specify the
inflammatory response in the AD brain, and (ii) elucidate whether these are altered in the presence of
circulating hormones. Our central hypothesis is that sex differences in the brain’s immune cells are driven by
sex chromosomes and gonadal steroid hormones, resulting in divergent inflammatory processes and therefore
AD onset and progression. The rationale for this project is that determining how genetic and hormonal
mediators contribute to sex differences in the neuroinflammatory processes in AD will provide a strong
scientific framework whereby new therapeutic strategies can be developed. The central hypothesis will be
tested by pursuing two specific aims: 1) Determine the contribution of sex chromosomes to the inflammatory
environment of the AD brain; and 2) Determine the organizational effects of sex hormones in establishing the
inflammatory response in the AD brain. Under the first aim, the 5xFAD mouse model of AD will be combined
with the Four Core Genotype (FCG) mouse to separate chromosomal and gonadal sex in the context of AD.
Inflammation will be assessed using biochemical and molecular techniques to examine immune cell activation
and neuronal health and survival. For the second aim, the brains of 5xFAD mice will be masculinized or
feminized neonatally to ascertain the effects of gonadal hormones on inflammatory processes. The innovation
of this project lies in: 1) the aspects of sex not previously considered in AD models, 2) the contribution of cell
differentiation during development to AD risk in ways not previously considered, and 3) the use of
methodologies to shift the disease paradigm away from protein functional differences towards expression
differences. Providing critical insights to the mechanisms giving rise to immune dysregulation and
neuroinflammation in AD are significant because they have the potential to become the basis for new
therapeutic strategies.

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