Basic Science and Pathogenesis.

Background: BIN1, the second strongest GWAS risk factor for late-onset Alzheimer's disease (AD), encodes a nucleocytoplasmic adaptor protein that plays many roles in multiple tissue and cell types. It is known that BIN1 can directly bind to tau in vitro, and neuronal BIN1 expression decreases in patients with AD. Accumulation of intracellular hyperphosphorylated tau is a hallmark pathogenic feature of AD and related tauopathies.

Basic Science and Pathogenesis.

Background: Microglia play significant roles in Alzheimer's disease (AD) pathophysiology. Current evidence suggests microglia may function in both protective and degenerative capacities, which has received little clarity from transcriptionally-characterised phenotypes uncovered from transgenic pathologies alone. BIN1 - the second-most significant risk gene for the development of late-onset AD (LOAD) - is expressed at high levels in neurons, oligodendrocytes and microglia.

Alzheimer's disease protective allele of modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication.

Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms remain largely unknown. For a strong AD-associated locus near (), we tied an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication.

YTHDF1 mediates translational control by m6A mRNA methylation in adaptation to environmental challenges.

Animals adapt to environmental challenges with long-term changes at the behavioral, circuit, cellular, and synaptic levels which often require new protein synthesis. The discovery of reversible N6-methyladenosine (mA) modifications of mRNA has revealed an important layer of post-transcriptional regulation which affects almost every phase of mRNA metabolism and therefore translational control. Many and studies have demonstrated the significant role of mA in cell differentiation and survival, but its role in adult neurons is understudied.

Alzheimer's disease risk allele of causes detrimental lipid droplets in microglia.

Despite genome-wide association studies of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci, the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC), we systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked risk allele to a previously unappreciated MG-specific role of in lipid droplet (LD) accumulation.