nbInnate Immunity Responses In Monocytes: Contribution To Neurodegeneration

Disruption of Innate Immunity Responses in Monocytes: Contribution to Neurodegeneration
ABSTRACT
Alzheimer’s disease (AD), characterized by elevated levels of β-amyloid (Aβ40 and Aβ42), is the leading cause
of dementia, prevailing in approximately 12% of the population worldwide. In turn, HIV-associated
neurocognitive disorders (HAND) prevail in 20-50% of people with HIV (PWH)1,2, despite the access to
combined antiretroviral therapy (cART). Monocyte recruitment to the brain promotes macrophage phagocytic
clearance of Aβ plaques and restoration of central nervous system (CNS) homeostasis (reviewed in3).
However, in HIV infection, peripheral monocytes infiltrate the compromised blood brain barrier (BBB) into the
CNS, triggering inflammation and neuronal damage4–7. Interestingly, HAND patients exhibit accumulation of
Aβ in the blood8 and in the brain9–12, despite the presence of infiltrated monocytes. HIV hijacks its target cells
to promote viral replication by impairing the interferon type I (IFN-1) signaling13,14. In AD, altered IFN-1
response decreases the recruitment of monocytes to the CNS15. IFN-1 signaling impairs insulin production16–
18, and dysregulated insulin signaling exacerbates Aβ plaque formation19,20. In turn, elevated levels of Aβ
contribute to insulin resistance and cognitive decline21. In HIV patients on cART, insulin resistance prevalence
is higher, compared to healthy individuals, which in turn is associated with worse neuropsychological
performance, suggesting that metabolic alterations could also contribute to the development of HAND22,23.
Thus, Aβ metabolism, insulin signaling, and cognitive impairment are interconnected. Due to their different
etiologies, the shared mechanisms underlying AD pathology and HIV neuropathogenesis are not well
understood. I hypothesize that impaired IFN-1 signaling in monocyte/macrophage (Mφs) alters their
phenotype and insulin receptor (IR) metabolism, contributing to cognitive impairment in HAND and in AD
patients. In this study, I will determine the contribution of the Mφs IFN-1 response to cognitive decline, through
the following aims: 1) Characterization of IFN-1 signaling and insulin receptor biology in monocytes from the
blood of AD and HAND patients, stratified by cognitive status; 2) using brain organoid models I will determine
whether monocytes are neuroprotective or neuroinflammatory upon HIV infection, using HIV-negative and
positive subjects’ monocytes; 3) I will determine the effect(s) of IFN-1 receptor modulation on Mφs phenotype,
and neuronal dysfunction in vitro using brain organoids. Results from this study will uncover novel mechanisms
involved in the crosstalk between the peripheral and CNS in neurodegenerative disorders. Further, our results
will help identifying candidates and/or targets for the development of effective therapies against cognitive
decline in HAND andAD. The proposed training plan is tailored to capitalize on my expertise in cellular biology
and viral immunology, and to expand my skill set with novel 3D brain organoids methodologies. The
multidisciplinary mentoring team is committed to provide career guidance, enrich my knowledge on new
techniques, and ensure my transition to independence in academia, specializing in neuroimmunology.

Grant Number: 5K22NS118975-05
NIH Institute/Center: NIH
Principal Investigator: Yisel Cantres-Rosario