Brain clearance of protein aggregates: a close-up on astrocytes

Abstract

Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts.Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown.Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation.

Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer’s Disease Treatment

“…Considering the dual function of glial cells in the brain—either mitigating Aβ-mediated neurotoxicity by improving its degradation and phagocytosis in normal conditions, as well as promoting neuroinflammation by triggering the release of inflammatory cytokines, thereby exacerbating neurodegeneration in AD patients [ 30 , 31 ], the effect of chronic cannabinoid therapy on astrogliosis was evaluated. Using GFAP and S100 to quantify reactive astrocytes, we observed a substantial increase in the number of astrocytes in the cerebral cortex, Ammon’s horn, and parahippocampal regions, ranging from 16–22 in the PG mice, 13–16 in the PDG animals, and 10–12 in the JG and JDG groups.…”

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

“…Astrocytes play an important role in the clearance of protein aggregates including α-syn (Giusti et al, 2024 ), which can involve the transfer of α-syn from neuron to astrocytes (Lee et al, 2010 ). We found a significant increase in reactive astrocytes number and/or sizes as indicated by an increase in % area GFAP immunoreactivity in both male and female A30P mice compared to WT, even at the pre-symptomatic stages at 2–4 months of age.…”

Clathrin mediated endocytosis in Alzheimer’s disease: cell type specific involvement in amyloid beta pathology

“…When treated with chlorpromazine, a pharmacological inhibitor of CME, astrocytes exhibit significantly decreased uptake of Aβ 1-42 and a partial rescue of Aβ 1-42 induced cell death ( Domínguez-Prieto et al, 2018 ). Additionally, astrocytes can take up and accumulate monomeric and oligomeric Tau ( Martini-Stoica et al, 2018 ; Brezovakova et al, 2022 ; Eltom et al, 2024 ; Giusti et al, 2024 ), though to the best of our knowledge the specific endocytic mechanisms involved have not been thoroughly examined and there is no strong link to CME specifically in astrocytes.…”