Autophagy is an essential degradation pathway in clearing abnormal protein aggregates in mammalian cells and is responsible for protein homeostasis and neuronal health. Several studies have shown that autophagy deficits occurred in early stage of Alzheimer's disease (AD). Autophagy plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its malfunction may lead to the progress of AD. By considering the above evidences, autophagy may be a new target in developing drugs for AD. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD and the potential therapeutic effects of autophagy modulators in AD.

Alzheimer's disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of "senile" plaques composed of amyloid-␤ (A␤) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gutmicrobiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of A␤ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiomebased therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a "lost link" in understanding and treating AD and call for future work.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.

The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate limiting step in the generation of β-amyloid (Aβ) during Alzheimer’s disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in the endocytic compartments, where the acidic pH is optimal for its activity. However mechanisms that regulate the endosome-to-TGN retrieval of BACE1 under physiological conditions remain unclear. Here we show the Par polarity complex containing Par3 and aPKC facilitates BACE1 retrograde trafficking from the endosomes to the TGN. We further show that Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498. Finally, we found that Ser498 phosphorylation promotes the interaction between BACE1 and PACS1, which is necessary for the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in the AD pathogenic process. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1, and shed light on the mechanisms of AD pathogenesis.