Sepsis and the Systemic Cytokine Storm in Aging and Alzheimer Disease Models - ABSTRACT Severe infection and sepsis accelerate cognitive decline in older Americans, especially those with incipient Alzheimer's disease (AD). Sepsis is known to induce a systemic inflammatory `cytokine storm', which wanes with time. However, this response often persists even after infection resolution in patients. We hypothesize that this systemic cytokine storm can potentially affect brain neuropathology in both pre-symptomatic AD patients and in older adults with no known cognitive deficits. In preclinical AD models, both amyloid and tau protein accretion and pathology are influenced by systemic inflammation. Less is known about the cognitive decline in sepsis survivors without incipient AD, known as sepsis-associated encephalopathy (SAE), and whether this is related to development of amyloid and tau neuropathology. Our overarching hypothesis is that sepsis and CCI induce unique local and systemic immunological responses that directly influence murine AD- and SAE-related pathology. We hypothesize that in incipient or prodromal AD, sepsis would specifically exacerbate brain health by exacerbating amyloid and tau neuropathology, while in cognitively normal older individuals, SAE outcomes would be exacerbated by aging pathways. We will test these hypotheses using 4 specific aims. In Aim 1) we will evaluate whether age plays a critical role in driving sepsis-induced neurodegeneration and loss of cognition (SAE) in wild-type mice. Here we propose to employ a survivable cecal ligation and puncture model of polymicrobial sepsis with daily chronic stress (CLP+DCS) in 6 month (mo) young and 18 mo older adult C57BL/6 (B6) mixed sex mice. Mice will be euthanized at 4 or 8 weeks post-sepsis for inflammatory and neuropathologic evaluation, which will include analysis of neuronal death, and brain inflammatory changes. Simultaneous spatial transcriptomic and proteomic profiling (NanoString GeoMx™) will allow assessment of brain region-specific alterations in response to the peripheral cytokine storm. Plasma will be analyzed for inflammatory cytokines and selected alarmins. Mice will also undergo cognitive assessment following their septic insult. In Aim 2) we will evaluate whether CLP+DCS-induced systemic inflammation alters Aβ deposition. Here we will use two APP transgenic mouse models – the fast progressing TgCRND8 mice and the slow progressing Tg.PrP HuAβ (APPsi) mice - to assess how systemic cytokine storm modulates amyloid deposition. In Aim 3) we will evaluate whether systemic inflammation exacerbates tau pathology. We will assess whether sepsis induces tau pathology in AD- relevant brain areas in the PS19 mice. Finally, in Aim 4) we will test whether prophylactic manipulation of the immune system alters SAE or AD-associated pathologies in selected animal models. Using an AAV-directed decoy sIL-10R, we will test whether suppressing IL-10 systemically or in the brain attenuates neuropathologic/behavioral outcomes. Additional mice will receive metformin orally during sepsis as it may be neuroprotective. This study will provide a mechanistic under-standing of sepsis-induced pathology, as well as differences in older adults with and without pre-existing AD.
