Beclin1 and autophagie in Alzheimers disease

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Alzheimers disease (AD) is the most common neurodegenerative disorder, hallmarked by extracellular amyloid plaques (composed of amyloid-beta (Abeta) peptide), neurofibrillary tangles, neuroinflammation and neurodegeneration. The amyloid cascade hypothesis states that deposition of Abeta in the brain parenchyma is one of the crucial steps in the development of AD. Microglia, the resident immune cells of the central nervous system are involved in two aspects of AD: the removal respectively the failure of removal of extracellular Abeta by phagocytosis and the production and release of cytokines. Next to the well-established enhanced neuroinflammation in the late stages of AD, recent data suggests a role for inflammation in the development of AD as well. A candidate process involved in both neuroinflammation and removal of Abeta is autophagy. The efficiency of autophagy seems to decline during aging. In addition, autophagy is a regulatory mechanism for the inflammatory response in macrophages. Beclin1, a crucial protein for autophagy, was also shown to be involved in receptor recycling and retromer recruitment for phagocytosis in vitro. Based on these data we postulate that Beclin1 is a key molecule in microglia, influencing neuroinflammation and Abeta deposition via autophagy and phagocytosis. This hypothesis will be tested by analyzing the impact of microglial Beclin1 loss in vivo employing two different approaches: inducible and constitutive loss of Beclin1.For the inducible model Beclin1 will be depleted at different time points with an inducible flox system targeting myeloid cells crossed to the established AD mouse model APPPS1+/- to determine the microglia-specific impact on autophagy and phagocytosis (aim 1), inflammation (aim 2) and Abeta deposition (aim 3) after complete loss of microglial Beclin1 in vivo. As additional system to pinpoint myeloid-driven effects an inducible flox system will be used to achieve a general loss of Beclin1.Next to that we will employ mice with a general constitutive heterozygous deletion of Beclin1 that will be crossed to APPPS1 mice, to mimic the situation in microglia from human AD patients. Again the effect of diminished Beclin1 levels in vivo on autophagy and phagocytosis (aim 1), inflammation (aim 2) and onset or progression of Abeta plaque deposition (aim 3) will be investigated.By using these two mouse systems this project will not only clarify the role of Beclin1 in microglial autophagy and phagocytosis in vivo but it is also very well suited to elucidate the causal and temporal relationship of microglial inflammation in AD and Abeta deposition.