Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease

Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors

AIMS: Developing beta cells are vulnerable to nutrient environmental signals. Early developmental processes that alter the number of pancreatic progenitors can determine the number of beta cells present at birth. Metformin, the most widely used oral agent for diabetes, alters intracellular energy status in part by increasing AMP-activated protein kinase (AMPK) signaling. This study examined the effect of metformin on the developing pancreas and beta cells. METHODS: Pancreatic rudiments at embryonic day 13.0 (E13.0) were cultured with metformin or AICAR (an AMPK activator) or vehicle control in vitro. In another set of studies, pregnant mice were treated with metformin throughout gestation. Embryonic (E14.0) and neonatal pancreata were then analyzed for their morphometry. RESULTS: In vitro metformin treatment led to an increase in the proliferation and number of PDX1(+) progenitors. These results were reproduced by in vitro culture of embryonic pancreas rudiments with AICAR, suggesting that AMPK activation was involved. Similarly, Metformin administration to pregnant dams induced an increase in both PDX1(+) and NGN3(+) progenitors in the embryonic pancreas at E14.0 and these changes resulted in an increased beta cell fraction in neonates. CONCLUSIONS: These results indicate that gestational metformin exposure modulates early steps of beta cell development (prior to E14.0) to increase the number of pancreatic and endocrine progenitors and these changes ultimately result in a higher beta cell fraction at birth. These findings are of clinical importance given that metformin is currently used for the treatment of gestational diabetes