Modulation of Neuronal Function in AD: The Role of Astrocyte p38 MAPK

ABSTRACT Advances in biomarker detection have unlocked unprecedented opportunity in the early detection and treatment of Alzheimer’s disease (AD), as highlighted by the recent FDA approval of two new anti-amyloid immunotherapies. The picture that has emerged from these successes is one in which cognitive preservation depends upon severing the link between initial amyloid accumulation and later involvement of tau. Multiple lines of evidence indicate that aberrant astrocyte activation is a critical link in this causal chain, and one that is likewise accessible to non-invasive biomarker detection. Work from our lab and others suggests that one particular regulator of astrocyte activation, the stress kinase p38α, may be crucially involved in this process. We therefore will test the central hypothesis that early astrocyte p38α signaling in response to Aβ accumulation enhances downstream microglial activation, neuronal damage, and eventual cognitive dysfunction. This will be tested in two complementary aims. Aim 1 will test the hypothesis that loss of astrocyte p38α rescues detrimental alterations in reactive astrocyte function and reduces AD-type neuropathology. Aim 2 will determine the clinical relevance of the animal findings by characterizing astrocyte p38α signaling in human brain across different levels of AD pathological burden. Inclusion of transcriptomic endpoints across both aims will enhance the discovery potential of the studies. If successful, this proposal will uncover important pathways underlying astrocyte pathological transformations, providing a framework for wider interrogation of astrocytic modulators that might find clinical utility for AD treatment.