Heat Shock Protein 70 as a Sex-Skewed Regulator of α-Synucleinopathy

Air pollution nanoparticle and alpha-synuclein fibrils synergistically decrease glutamate receptor A1, depending upon nPM batch activity

“…Consistent with the literature [ 29 , 30 , 33 , 34 , 53 ], intra-OB injection of α-syn PFFs caused α-syn propagation to other ipsilateral regions, including AON, PCX, and AMY ( Fig. 2 , Fig.…”

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes

“…We tested if transient PLX5622 exposure moderates the behavioral, biochemical, and histological consequences of α-synucleinopathy in our model of limbic Lewy body disease ( Bhatia et al, 2021 ; Mason et al, 2016 ; Mason et al, 2019 ; Miner et al, 2022 ). In the PFF model, the density of Lewy-like pathology typically peaks ~8 weeks later in first-order afferents ( Duffy et al, 2018b ; Patterson et al, 2019 ; Paumier et al, 2015 ; Stoll and Sortwell, 2022 ).…”

“…5l – o ). We chose the hippocampus for region-specific microglia and neuron cocultures because primary hippocampal neurons have been used in well-standardized PFF in vitro work ( Volpicelli-Daley et al, 2014 ) and we have validated this model in our hands ( Bhatia et al, 2021 ; Miner et al, 2022 ). First, we show that our hippocampal microglia cultures responded to canonical stimuli, in that exposure to interleukin-4 (IL4) elicited an increase in anti-inflammatory CD206, whereas exposure to a cocktail of lipopolysaccharide and interferon-γ (LPS/IFNγ) elicited an increase in proinflammatory iNOS and CD16 ( Fig.…”

“…The PFF preparation contained 0.11 picograms LPS per microgram protein (communication from Dr. Luk). PFFs were sonicated in a waterbath (Bransonic series model M1800, Branson Ultrasonics Corporation, Danbury, CT) for 60 mins immediately prior to use, as described in our prior work ( Bhatia et al, 2021 ; Mason et al, 2016 ; Mason et al, 2019 ; Miner et al, 2022 ; Nouraei et al, 2018 ). Our sonication protocol results in a mean fibril length of 39.8 nm and a median length of 35.2 nm by transmission electron microscopy [quantified from images shown in ( Mason et al, 2016 )].…”

“…Previously, we found that PFF infusions targeted to the rear of the OB ( i.e. , centered in the bulbar AON) lead to limbic inclusions that are immunoreactive for phosphorylated α-synuclein (pSer129) and ubiquitin, and are stained with the Proteostat dye for amyloid protein aggregations ( Bhatia et al, 2021 ; Mason et al, 2016 ; Mason et al, 2019 ; Miner et al, 2022 ). Thus, we leveraged our mouse model to test the hypothesis that transient dietary exposure to PLX5622 would mitigate limbic α-synucleinopathy in aged mice of both sexes.…”