Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

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Abstract: Alzheimer’s Disease (AD) is a debilitating conditioned marked by accumulation of Ab and hyperphosphorylation of tau proteins thought to lead to neurodegeneration and cognitive decline. It has been hypothesized that Ab accumulation and tauopathy might result in damage to blood vessels that make up the blood brain barrier (BBB), which is estimated to contribute to ~50% of all dementias worldwide, including AD. Such BBB damage is thought to result in disease pathogenesis by increasing brain permeability and peripheral immune infiltration. Animal models of AD-related pathology, which rely on the overexpression or knock-in of established genetic mutations, have confirmed that the accumulation of Aβ and tau does indeed result in blood vessel abnormalities and blood- brain barrier (BBB) breakdown (Fig 1), which is associated with behavioral symptoms including cognitive dysfunction. In addition to cognitive decline, many AD patients also experience severe neuropsychiatric symptoms such as depression and anxiety. While the mechanisms of comorbid neuropsychiatric symptoms with AD are not well known, we have shown that chronic stress—a known risk factor for AD in humans—can in fact damage the BBB. Under the parent R01MH104559, my lab has been investigating whether pro-inflammatory cytokines such as interleukin 6 (IL-6) or immune cells themselves may diffuse more readily into the brain of stressed mice due to vascular damage. We have found that stress reduces expression of the tight junction protein claudin 5 (CLDN5) and leads to breakdown of the endothelial barrier allowing greater entry of IL-6 directly into brain reward regions like the nucleus accumbens (NAc) to impair social behavior and responses to natural rewards [15]. Interestingly, genetic mouse models of AD-related pathology confirm that they are indeed more sensitive to the behavioral effects of stress and exhibit age-related degeneration of the BBB, which leads to increased permeability. In this supplement we will examine the effects of chronic social stress on BBB integrity and stress-induced behaviors in well-established mouse models of AD-related pathology.