Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits a mouse model of DLB/PD

Abstract

ɑ-synuclein (ɑ-syn) progressively accumulates in age related neurodegenerative diseases such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Although ɑ-syn spreading has been extensively investigated, the role of aging in the manifestation of disease remains unclear. Thus, we explored the role of aging in the pathogenesis of synucleinopathies in a mouse model of DLB/PD initiated by intrastiatal injection of ɑ-syn preformed fibrils (pff). We found that aged mice showed more extensive accumulation of ɑ-syn and behavioral deficits that was associated with greater infiltration of T cells and microgliosis. Microglial inflammatory gene expression induced by ɑ-syn-pff injection in young mice had hallmarks of aged microglia, indicating that enhanced age-associated pathologies may result from inflammatory synergy between aging and the effects of ɑ-syn aggregation. We propose that aging related inflammation influences outcomes of pathological spreading of ɑ-syn and suggests that targeting immune responses might be important in developing treatments for DLB/PD.

Rapid iPSC inclusionopathy models shed light on formation, consequence and molecular subtype of α-synuclein inclusions

“…Such non-cell-autonomous effects will be critical to examine in our models. For example, the toxicity of PFFs may be deeply related to neuroinflammation(Garcia et al, 2022; Iba et al, 2022; Stoll and Sortwell, 2022). The relative lack of toxicity we see with PFFs in our neurons departs from what is seen in vivo in mouse models(Luk et al, 2012; Mao et al, 2016; Park et al, 2021) and may relate to a lack of inflammatory responses.…”

Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson’s disease

“…This phenomenon has been modeled and reproduced in vivo using pre-formed fibrils (PFFs) comprised of in vitro assembled -sheet-rich -synuclein. Once injected into the brain, PFFs recapitulate aspects of PD Lewy body pathology (Henderson et al, 2019), causing dysregulation in multiple cellular and molecular pathways (Goralski et al, 2024) and leading to neuroinflammation (Earls et al, 2019;Iba et al, 2022), metabolic impairment (Creed et al, 2022;Lu et al, 2022) and circuit dysfunction (Blumenstock et al, 2021). This can be analyzed to measure the progression of pathology between anatomically connected neuronal populations, including in cortical neurons projecting to the striatum (Henderson et al, 2019;Luk et al, 2012).…”