Transcriptomic and Circuitry Aberrations in Alzheimer’s Disease

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Project Summary In Alzheimer’s disease (AD) research, a big challenge is the identification and targeting of key molecules in critical neural circuits that play a causal role in cognitive impairment at the early stage before global neurodegeneration. We hypothesize that transcriptional downregulation of selective neuronal genes in early AD initiates the loss of synaptic function in specific brain circuits, leading to cognitive decline. In Aim 1, we will identify transcriptomic changes at the early stage of AD using human postmortem tissues and iPSC-derived cortical neurons. Comprehensive bioinformatic analyses of large-scale bulk and single-cell RNAseq data from postmortem human with ‘early-pathology’ and ‘late-pathology’ of AD will be performed to identify prominent changes in gene networks, molecular pathways and biological processes at different stages. Given the limitation of postmortem tissues in capturing early molecular alterations, we will also profile transcriptional changes using human cortical neurons differentiated from iPSCs of sporadic AD patients. Based on our preliminary data, the loss of selective presynaptic and postsynaptic genes involved in vesicle release and glutamatergic/GABAergic transmission is the major early change in cortical neurons of AD patients. In Aim 2, we will identify electrophysiological changes using AD mouse models and iPSC-derived cortical neurons from AD patients. We will use in vivo multichannel recording of action potential spikes, optogenetic isolation of neural pathways and ex vivo patch-clamp recording of synaptic currents in AD mouse models to obtain the high-resolution mapping of cognitive circuits that go awry at various stages. In Aim 3, we will identify intervention strategies to rescue AD- associated functional deficits in AD mouse models and iPSC-derived cortical neurons from AD patients. Guided by the identified molecular and circuitry changes in AD, we will use viral-based approaches to normalize gene expression or neuronal activity in specific circuits, and examine the impact on synaptic transmission and cognitive behaviors in AD mouse models. This study will uncover transcriptomic and circuitry aberrations in early stage of AD, and help to develop mechanism-based therapeutic strategies to mitigate synaptic deficits and improve cognition.