Spreading of Tau and other corrupted proteins through the gut‐brain axis

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia. However, although the clinical and pathological aspect of the disease are thoroughly characterized, the pathophysiological mechanism underlying the progressive neurodegenerative process is not well understood. In consequence, there is no cure and a disease‐modifying treatment is lacking. It is therefore imperative to identify the earliest signs of disease pathology to pave the way to identify the triggering molecular factors of the disease and the mechanisms underlying molecular spreading of toxic assemblies. Our search for these key clues in the periphery is founded on the fact that peripheral dysfunction, particularly in the gastrointestinal (GI) system, can arise decades before the onset of the classic symptoms in neurodegenerative disorders. In fact, the risk of AD increases significantly in patients with inflammatory bowel disease (IBD) when compared with the non‐IBD population. Furthermore, Tau accumulates in Crohn’s Disease guts and in sigmoid colon of AD and FTD patients. Therefore, we are investigating the physiological and molecular mechanisms that support Tau spreading in the prodromal stages and, particularly, along the gut‐brain axis.MethodTo test whether corrupted proteins expressed in the gut will spread to the brain, we employed the Gal4/UAS system and expressed wild type human Tau in selected populations of gut epithelium cells. We then monitor behavior on aging flies expressing Tau in the gut epithelium using Drosophila activity monitors (DAM) and analyzed their circadian patterns of activity along with several sleep parameters.ResultWe observed that flies selectively expressing full length (2N4R) human Tau in enteroendocrine cells of the gut exhibited a significant impairment in their daily activity pattern that specifically affected their behavior during the light phase (day) but not during the dark period (night). Interestingly, these flies also showed an increased sleepiness during the day without affecting their nocturnal sleep pattern. The onset of these behavioral changes appears to occur as early as 10 days after eclosion.ConclusionOur results support the presence of spreading mechanisms for Tau from gut epithelial cells to the brain; hence, affecting the neuronal physiology that sustain daily activity patterns.