Thursday, October 17, 2024
10/17/2024
After decades of intense effort, two disease-modifying drugs for Alzheimer's disease (AD) have been recently approved by the FDA: aducanumab and lecanemab. Although these drugs represent a major advance in AD therapeutics, they have limitations: modest clinical benefit and side effects (brain edema and hemorrhage). Additional therapies targeting new AD mechanisms are desperately needed to improve clinical benefit and reduce side effects. Moreover, precision medicine for AD will require a panoply of drugs targeting different AD mechanisms that will allow tailoring a combination therapy to the individual patient. The goal of this R01 is to explore the therapeutic potential of inhibiting one such AD mechanism, that of Aβ-induced membrane damage. Amyloid plaques consisting of the β-amyloid (Aβ) peptide and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein are hallmarks of AD brain. Amyloid plaques accumulate many years before NFTs arise. Aβ appears to be toxic to neurons surrounding plaques, causing molecular and cellular alterations that lead to tau pathology, synapse loss, neuron death, and ultimately memory impairment and dementia. However, the mechanism connecting Aβ with tau hyperphosphorylation and pathology is unknown and one of the great mysteries of AD. A clue could come from dystrophic neurites (DNs), an understudied AD pathology that is mostly of axonal origin and tightly associated with the borders of amyloid plaques. DN morphology suggests that direct axon contact with the Aβ plaque is necessary for the formation of DNs. Our results indicate that Aβ interaction with the axon plasma membrane causes plasmalemma damage, Ca2+ leakage, kinase activation, microtubule disruption, axonal transport impairment, tau hyperphosphorylation, and DN formation. Importantly, our preliminary results show that overexpression of the membrane repair protein annexin A6 in the 5XFAD mouse model of amyloid pathology reduces the formation of DNs and the accumulation of tau phosphorylated at threonine 181 (p-tau181), an early biomarker of amyloid pathology in AD. Other work suggests that DNs are crucibles of AD tau phosphorylation, seeding, and spreading. In this R01, we will investigate annexin A6-mediated membrane repair following Aβ-induced membrane damage and DN formation (Aim 1) and reduction of p-tau accumulation and the seeding and spreading of AD tau (Aim 2) in vitro and in vivo. Finally, we will investigate recombinant annexin A6-mediated membrane repair and reduction of DN formation, p-tau accumulation, and AD tau seeding and spreading (Aim 3). We will use a combination of molecular (immunoblot analysis, biochemical assays), cellular (laser injury, dye penetration, immunohistochemistry, calcium imaging, EM), electrophysiological (LTP) and cognitive (water maze, fear conditioning, novel object recognition, Y-maze) approaches to accomplish these Aims. These experiments will serve as therapeutic proof-of-concept supporting annexin A6 for the prevention or treatment of AD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
