Calcineurin and Inflammatory Signaling Processes in Aging and Alzheimer's Disease

Mounting evidence suggests that comorbid vascular contributions to cognitive impairment and dementia (VCID) may complicate the treatment of Alzheimer’s disease (AD)-related dementia. Our overarching hypothesis is that AD and VCID sequelae converge at the level of activated astrocytes, providing a common druggable target for a wide range of dementias (i.e. AD alone, VCID alone, and mixed dementia). Central to this hypothesis is the Ca2+ -dependent phosphatase, calcineurin (CN), which appears at high levels in activated astrocytes and positively regulates multiple components of the activated astrocyte phenotype through direct interactions with NFAT transcription factors. We, and others have shown that hyperactivation of CN/NFAT occurs in astrocytes during early stages of cognitive decline in humans and mice with AD-like pathology and is linked to glutamate-dependent hyperexcitability. However, little is known about astrocytic CN/NFAT in VCID, presenting a critical knowledge gap in our understanding of mixed dementia. New preliminary data obtained from human cerebrovascular pathology cases and from a novel diet-based VCID mouse model, suggest that hyperactive CN/NFAT signaling also arises with cerebrovascular pathology. Based on these observations, we predict that combined AD and VCID pathology will exacerbate aberrant CN/NFAT signaling leading to a “neurotoxic” astrocyte phenotype, characterized by the loss of EAAT2/Glt-1 glutamate transporters and impaired glutamate uptake. We further predict that normalization of the CN/NFAT/Glt-1 axis, using cell-type specific AAV vectors and novel pharmacologic agents, will alleviate neuronal and cerebrovascular abnormalities in AD, VCID, and mixed AD/VCID. Our overarching hypothesis and corollary predictions will be tested using human biospecimens and relevant mouse models including the hyperhomocysteinemia (HHcy) model of VCID and the 5xFAD model of AD. Aim 1 will test the hypothesis that mixed AD and VCID pathologies converge to exacerbate CN/NFAT hyperactivity in astrocytes, leading to a neurotoxic astrocyte phenotype. Aim 2 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis drives cerebrovascular dysfunction in AD, VCID, and mixed AD/VCID models. Aim 3 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis drives hyperexcitability in AD, VCID, and mixed AD/VCID models. These aims will be pursued using novel reagents, and cutting-edge interdisciplinary approaches. This work is essential for assessing the role of astrocytic CN/NFATs in VCID and mixed pathology and may help stimulate the development of astrocyte-targeted approaches for treating a broad range of dementia cases.