Introduction:
Parkinson’s Disease (PD) is progressive neurodegenerative condition with unknown aetiology, recognised to have a debilitating effect on motor function. While PD is primarily characterised by the brain-wide accumulation of the protein α-synuclein into Lewy Bodies (LBs), there is also notable aggregation of associated amyloid-β (Aβ) pathology reported1. This is linked to a worse disease prognosis2 and symptomatic dementia (PDD)3, where up to 50% of PD patients develop dementia ten years within of their initial diagnosis.
Glial responses, particularly astrocytes, are known to be dysfunctional in PD. Although transcriptomic profiles of astrocytes have been noted to change in PD4, the field is yet to characterise their disease-specific morphological features5. To better understand dysfunctional astrocytic responses in PD, we investigated the morphological changes of astrocytes in differing proximity to LBs and/or amyloid plaques using human post-mortem tissue, and whether this varying morphology could underlie patient outcomes.
Materials and Methods:
Post-mortem tissue blocks of the medial temporal gyrus of the temporal cortex were provided by the Parkinson’s UK Brain Bank at Imperial College London (REC: 23/WA/0273). Five cases with a PD/PDD diagnosis from our full cohort of controls (n = 10), PD (n = 10), and PDD cases (n = 10) were used for initial analysis.
We conducted multiplex immunofluorescence staining for astrocytes (S100β), α-synuclein (α–syn) and amyloid plaques (Aβ) for each case. Imaged grey-matter ROIs from these stains went through a segmentation pipeline where we analyzed the morphological features of astrocytes near LBs (within 30µm) and/or amyloid plaques (within 40µm), or far from them. A one-way ANOVA was used to assess for significance with a Turkey HSD post hoc test used thereafter. Differences in astrocytic morphology between PD vs PDD were tested using an unpaired t-test.
Results:
When near either LBs or amyloid plaques, the size of astrocytes reduced, illustrating a trend of astrocytic morphology feature changes in proximity to pathology. Total number and length of astrocytic branches increased progressively as astrocytes were in close proximity to either an LB or an amyloid plaque, while the highest branch and length counts were in cells that were near both an amyloid plaque and a LB.
When we investigated whether these morphological features differed in cells of patients diagnosed with PD vs. PDD, we found that astrocytes from PDD cases were larger on average as compared to PD, and the total number and length of astrocytic branches were significantly higher in PDD cases vs PD (p < 0.05).
Conclusions:
Our results indicate a trend of morphological changes in astrocytes from the temporal cortex of PD patients in proximity to α-synuclein-containing LBs and amyloid plaques. When differentiated by diagnosis, astrocytes from PDD brains illustrate significantly different morphological features as compared to PD brains, alluding to varied glial responses in differing patient outcomes.