The Role of Reactive Astrocytes in the Propagation and Clearance of Tau in Alzheimer's Disease

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT While for decades reactive astrocytes surrounding amyloid-β (Aβ) plaques and phospho-tau (pTau) neurofibrillary tangles in Alzheimer’s disease brains have been identified by their high levels of the cytoskeletal intermediate filament glial fibrillary acidic protein (GFAP), the downstream effects of this GFAP upregulation on the progression of these AD neuropathological changes remain obscure. Importantly, our preliminary data from an Alzheimer’s disease tau transgenic mouse model indicate that GFAP overexpression in astrocytes actually attenuates pTau hippocampal pathology, suggesting that GFAP upregulation by reactive astrocytes in Alzheimer’s disease may be a neuroprotective response of astrocytes against pTau-induced neurotoxicity rather than a ubiquitous, non-specific epiphenomenon accompanying the neurodegenerative process. Our central hypothesis in the present proposal, supported by these preliminary data, is that GFAP upregulation by astrocytes ameliorates trans-synaptic neuron-to-neuron pTau propagation through increasing pTau uptake and clearance. Further rationale for this hypothesis includes the following facts: (1) Alzheimer’s disease progression is driven by the trans-synaptic neuron-to-neuron propagation of proteopathic pTau species along neural networks; (2) astrocyte peri-synaptic processes are integral part of tripartite excitatory synapses and GFAP is critical for intracellular vesicular transport to and from these peri-synaptic processes; (3) astrocytes have been implicated in the clearance of pTau and other misfolded protein aggregates; and (4) GFAP has been involved in chaperone- mediated autophagy through its interaction with LAMP2A at the lysosomal membrane—suggesting a link between GFAP levels and astrocyte proteostasis. Our overall goal is to elucidate the contribution of reactive astrocytes to Alzheimer’s disease progression and evaluate their potential for neuroprotective therapeutic applications. We will investigate whether astrocyte GFAP has a protective effect on neuron-to-neuron propagation of pTau across synapses in an in vivo mouse model of Alzheimer’s disease-like pTau seeding and propagation (Aim #1); determine whether increasing GFAP levels enhances pTau uptake and clearance by astrocyte cell models (Aim #2); and interrogate the GFAP interactome with quantitative proteomics to learn about putative molecular mediators of GFAP effects on proteostasis (Aim #3). Since the extent of pTau neurofibrillary tangle pathology strongly correlates with the severity of cognitive decline associated with Alzheimer’s disease, filling this fundamental knowledge gap could further our understanding of the role of reactive astrocytes in Alzheimer’s disease clinical progression. Upon successful completion of these aims, our expected outcome is to have delineated the roles of GFAP upregulation by reactive astrocytes in both pTau propagation along neural networks and pTau uptake and clearance by astrocytes.