Westaway, D. | bioRxiv Science

bioRxiv2022

Amyloid-β seeding effects are dependent on the presence of knock-in genes in the AppNL-G-F mice.

Alzheimers disease (AD) is characterized by the prion-like propagation of amyloid-{beta} (A{beta}). However, the role of A{beta} in cognitive impairment is still unclear. To determine the causal role of A{beta} in AD, we intracerebrally seeded the entorhinal cortex of two-month-old AppNL-G-F mouse model with an A{beta} peptide derived from patients who died from rapidly progressing AD. When the mice were three and six months of age, or one- and four-months following seeding, respectively, spatial learning and memory were tested using the Morris water task. Immunohistochemical labeling showed seeding with the A{beta} seed increased plaque size one month following seeding, but reduced plaque counts four months following injection compared to the control seeded mice. A significant increase in microgliosis was found. However, we found no correlation between pathology and spatial performance. The results of the present study show that seeding human tissue with or without A{beta} alters learning and memory ability, A{beta} plaque deposition, plaque size, and microgliosis in the AppNL-G-F knock-in model, and these effects are dependent on the presence of a humanized App gene and the presence of A{beta} in the seed. But these pathological changes were not initially causal in memory impairment.

animal behavior and cognition↗

bioRxiv2020

Tau conformers in FTLD-MAPT undergo liquid-liquid phase separation and perturb the nuclear envelope

Recent studies show that a single MAPT gene mutation can promote alternative tau misfolding pathways engendering divergent forms of frontotemporal dementia and that under conditions of molecular crowding, the repertoire of tau forms can include liquid-liquid phase separation (LLPS). We show here that following pathogenic seeding, tau condenses on the nuclear envelope (NE) and disrupts nuclear-cytoplasmic transport (NCT). Interestingly, NE fluorescent tau signals and small fluorescent inclusions behaved as demixed liquid droplets in living cells. Thioflavin S-positive intracellular aggregates were prevalent in tau-derived inclusions with a size bigger than 3 m2, indicating that a threshold of critical mass in the liquid state condensation may drive liquid-solid phase transitions. Our findings indicate that tau undergoing LLPS is more toxic amongst a spectrum of alternative conformers; LLPS droplets on the NE that disrupt NCT serve to trigger cell death and can act as nurseries for fibrillar structures abundantly detected in end-stage disease.

neuroscience↗