A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice.

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain.

Nrf2 deletion results in impaired performance in memory tasks and hyperactivity in mature and aged mice.

Oxidative stress has been implicated in both the functional and cognitive decline associated with neuropsychiatric diseases and aging. A master regulator of the body's defense mechanism against oxidative stress is nuclear factor erythroid 2-related factor (NRF2). Here we investigated the effects of NRF2 deletion on motor and cognitive performance in "Aged" mice (17-25 months old) as compared to "Mature" mice (3-15 months old). We observed that the Aged Nrf2-/- mice were hyperactive and exhibited impaired acquisition of an active avoidance response. Furthermore, the Mature mice also displayed a hyperactive phenotype and had impaired working memory in the probe trial of the water radial arm maze. Overall, it appears that NRF2 may be implicated in memory and activity functions and its deletion exacerbates deficits associated with aging. These observations provide a model for assessing the role of oxidative stress in age-related disorders.