Alzheimer?s disease (AD) lies on a continuum with dynamic neurobiological and pathological symptoms / markers, therefore we need to identify novel biomarkers to optimize targeted therapies for improved patient care. Increasing evidence support that age-related accumulation of senescent cells, chronic inflammation, and altered glutamate neurotransmission represent inter-related mechanisms that increase the risk for developing AD. Understanding this interaction is crucial to identifying novel therapeutic targets for improving patient outcome. Existing data support the proteinopathy-induced senescent cell hypothesis of AD proposed by Golde and Miller, whereby soluble and insoluble A? activates the innate immune system triggering a self-reinforcing cycle of pro-inflammatory signaling and cellular senescence, ultimately leading to neurodegeneration (possibly through altered glutamate neurotransmission), and cognitive decline in AD. However, the role of A?42 and glutamate neurotransmission in this self-reinforcing cycle, and whether decreasing cellular senescence and / or inflammation can prevent cognitive decline, is unknown. Addressing this gap in knowledge may be key to identifying underlying mechanisms and therapeutics that have the ability to alter functional outcomes. To address our central hypothesis that reducing the burden of senescent cells and shifting the profile of adipokines and cytokines from pro- to anti-inflammatory will restore glutamate neurotransmission and thereby slow or prevent AD-related cognitive decline, we will target cellular senescence (Aim 1) or systemic inflammation (Aim 2) at two distinct time points during disease progression; 1) 4-5 months of age, elevated soluble A?42, some plaque buildup, and little to no cognitive decline, and 2) 16-17 months of age, significant plaques accumulation and cognitive decline. This will allow us to examine both the long term and short term effects of these interventions. The studies will help determine the mechanisms by which brain aging and A?42 impacts the development and progression of AD and may lead to interventions through identification of novel, disease stage specific biomarkers and optimal therapeutic treatment windows.
In the proposed studies, we will examine the influence of cellular senescence and inflammation on hippocampal extracellular glutamate and cognition in APPNL-F/NL-F and APP/PS1 mice, as it relates to Alzheimer?s disease. We hypothesize that reducing the burden of senescent cells and shifting the profile of adipokines and cytokines from pro- to anti-inflammatory will restore glutamate neurotransmission and thereby slow or prevent AD-related cognitive decline. These experiments have the potential to improve scientific knowledge and lead to preventative interventions through identification of novel therapeutic targets with the potential to improve patient outcome.
| Hascup, Erin R; Broderick, Sarah O; Russell, Mary K et al. (2018) Diet-Induced Insulin Resistance Elevates Hippocampal Glutamate as well as VGLUT1 and GFAP Expression in A?PP/PS1 Mice. J Neurochem : |
