2024
Alzheimer’s disease (AD) is the most common cause of dementia, characterized by extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tau tangles (NFT). One of the major mechanisms that influence AD pathologies is neuroinflammation regulated by the brain glial cells, including astrocytes. Astrocytes are one of the most abundant cell types in the brain, and they have several functions, including regulating ionic gradients for neuronal activity and providing neuronal metabolic support. In response to AD pathologies, astrocytes alter their gene expression and morphology, becoming inflammatory. In AD, astrocytes’ inflammatory response develops early in the disease, colocalizing with Aβ plaques and increasing linearly with NFT. However, despite a compelling association between astrocytes and AD development and progression, their impact on disease pathologies and therapeutic potential remains largely unknown. Our studies provide evidence that astrocytes promote AD pathologies by increasing the α2-N+/K+ ATPase (NKA) ionic pump expression and activity. By utilizing AD mouse models of pathology together with pharmacological and genetic knockout approaches, we demonstrated that inhibition or astrocytic NKA knockout decreased tau pathology and Aβ plaques. However, the NKA is also expressed peripherally in cardiac muscle, limiting its therapeutic potential. Therefore, we aim to investigate the NKA mechanism regulating astrocytes that influence AD pathology, providing new targets that overcome this limitation. The primary NKA role is maintaining ionic gradients, which consume large amounts of cellular energy under normal conditions. Consequently, we hypothesized that, in AD, the increased astrocytic NKA activity alters astrocyte metabolism and activates the metabolic sensor AMP-activated protein kinase (AMPK). The current study investigates astrocyte AMPK metabolic pathways, which may provide methods to modulate neuroinflammation as a therapeutic strategy for AD.
Gilbert Gallardo, Ph.D.
