Hippocampal subfield vulnerability to α-synuclein pathology precedes neurodegeneration and cognitive dysfunction

Cognitive dysfunction is a salient feature of Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of α-synuclein fibrils in vivo, we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of α-synuclein fibrils within the mouse forebrain, we measured the burden of α-synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to α-synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of α-synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with α-synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of α-synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction.


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anti-pS129-α-synuclein (ab51253; Abcam) mouse anti-NeuN (MAB377; Sigma-Aldrich) rabbit anti-GFAP (ab227761; Abcam) nature portfolio | reporting summary April 2023ValidationAll antibodies are from commercial sources with ample data describing their specificity on the manufacturers website, in addition to validation data in our prior publications.to confirm that the raw and calibrated dates are available in the paper or in Supplementary Information.nature portfolio | reporting summary April 2023 Could the accidental, deliberate or reckless misuse of agents or technologies generated in the work, or the application of information presented in the manuscript, pose a threat to: involve any of these experiments of concern: No Yes Demonstrate how to render a vaccine ineffective Confer resistance to therapeutically useful antibiotics or antiviral agents Enhance the virulence of a pathogen or render a nonpathogen virulent Increase transmissibility of a pathogen Alter the host range of a pathogen Enable evasion of modalities Enable the weaponization of a biological agent or toxin Any other potentially harmful combination of experiments and SoftwareDescribe the software used to collect and analyze the ChIP-seq data.For custom code that has been deposited into a community nature portfolio | reporting summary Specify type(mass univariate, multivariate, RSA, predictive, etc.)and describe essential details of the model at the first and second levels (e.g.fixed, random or mixed effects; drift or auto-correlation).Define precise effect in terms of the task or stimulus conditions instead of psychological concepts and indicate whether ANOVA or factorial designs were used.CorrectionDescribe the type of correction and how it is obtained for multiple comparisons (e.g.FWE, FDR, permutation or Monte Carlo).Report the measures of dependence used and the model details (e.g.Pearson correlation, partial correlation, mutual information).