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Fraccaroli, I.

Publications and source records attributed to Fraccaroli, I..

2 recordsLinked to original sources

APP-KI mice do not display the hallmark age-dependent cognitive decline of amyloid diseases

APP knock-in (KI) mice serve as an exciting new model system to understand amyloid beta (A{beta}) pathology, overcoming many of the limitations of previous overexpression-based model systems. The APPSAA mouse model (containing the humanized APP with three familial Alzheimers disease mutations) and the APPWT control are the first commercially available APP KI mice within the United States. While APPSAA mice have been shown to develop progressive A{beta} pathology and neuroinflammation, behavioral changes, particularly in cognitive functions, have yet to be described. Therefore, we performed an in-depth longitudinal study over 12 months, assessing cognition in these two strains, as well as assessments of motor and GI function. We surprisingly note no overt, progressive cognitive impairment or motor deficits. However, we do observe a significant increase in fecal output in APPSAA mice compared to APPWT at 12 months old. These data provide a baseline for these models behavioral attributes. HighlightsO_LIAPPSAA and APPWT knock-in mice do not display age related cognitive decline C_LIO_LIFecal output appears altered by APP genotype, but no other measure of GI function is impacted. C_LIO_LIBoth genotypes behave equally in motor function tests C_LI

neuroscience↗

Overexpression of human alpha-synuclein leads to dysregulated microbiome and metabolites with ageing in a rat model of Parkinson disease

Since Braaks hypothesis stating that sporadic Parkinsons disease follows a specific progression of the pathology from the peripheral to the central nervous system and can be monitored by detecting accumulation of the alpha-Synuclein protein. There is growing interest in understanding how the gut (commensal) microbiome can regulate alpha-Synuclein accumulation which can lead to PD. We studied a transgenic rat model overexpressing the human alpha-Synuclein and found that the protein overexpression resulted in gut alpha-Synuclein expression and aggregation in the gut neurons with advancing age. A progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young transgenic rat model and interestingly this ratio was then increased with aging. This observation was accompanied in older animals by intestinal inflammation, increase gut permeability and a robust alteration in metabolites production characterized by the increase of succinate level in the feces and serum. Manipulation of the gut bacteria by short-term antibiotics treatment revealed a complete loss of short-chain fatty acids (SCFAs) and reduction in succinate levels. Although antibiotics treatment did not change alpha-synuclein expression in the enteric nervous system of the colon, it can reduce alpha-synuclein expression in the olfactory bulb of the transgenic rats. In summary, synchronous with ageing, our data emphasize that the gut microbiome dysbiosis leads to a specific alteration of gut metabolites which are reflected in the serum and can be modulated by the environment.

neuroscience↗