Cell-type specific risk and resilience in Alzheimer’s disease and aging

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with distinct histological and behavioral hallmarks but its cell-type basis is not clear. Recent discoveries now provide compelling rationale that constituent cell types bear a non-uniform risk profile as a function of disease and age. Human post- mortem study showed inhibitory interneurons (IN) and excitatory pyramidal neurons (IN) undergo differential alterations in gene expression in AD and mouse brain imaging study observed progressive cytological dedifferentiation of synapse architecture due to aging. These results dovetail with our discovery that the differential expression of six gene categories, synergistically involved in synaptic communication specifies neuron-type identity and their diverse morpho-physiological properties. Our central hypothesis is that the distinct transcriptomic identity that bestows unique cell-type properties also confers an inherent risk and resilience to AD risk factors, such as age, sex and genetic makeup. We posit that an altered cell-type specific transcriptome underlies the disparate response of inhibitory and excitatory neuron subtypes in AD and the dedifferentiation of synapses in aging. Through cross-disciplinary systems biology approaches we will identify the vulnerable cell-types in AD, establish cell-type specific AD signatures and further investigate biological relationship between healthy aging and AD pathology. Aim-1 will test the hypothesis that diverse brain cell subclasses confers differential risk through distinct transcriptomic response to progressive stages of AD and aging. A subclass specific longitudinal approach will allow us to prioritize for cells that are fundamental to the genesis of AD. We will determine age-dependent vulnerability in 3xTg-AD mouse by single- cell RNA-Seq (scRNA-Seq) of eight genetically labeled subclass in three major AD associated brain areas, brain-stem, entorhinal cortex, hippocampus and frontal cortex at 3, 6 and 15 months. Aim-2 will test the hypothesis that excitatory PNs and inhibitory INs have differential anatomical, morphological and cell survival trajectories in AD and aging. Synapses in neural circuits control behavior and their progressive dedifferentiation have been implicated in aging and dementia. As the molecular composition of synapses are distinct for each neuron-type they will be differentially impacted by AD and age. We will perform whole brain light-sheet microscopy on PN and IN in 3xTg-AD mouse across three time points 3, 6 and 15 months to capture the subclass specific dynamics of progressive pathological changes in AD. Aim-3 will test the hypothesis that cell specific glycosylation codes confers vulnerability to proteinopathy in AD and aging. Plaques and neurofibrillary tangles are AD hallmarks, however cell specific vulnerability is unknown. Differential expression of heparin sulfate (HS) enzymes create HS diversity akin to a “glycosylation code” that predisposes some cells to form aggregates while protecting others. In 3xTg-AD multiplexed RNA in-situ will measure HS biosynthetic enzyme transcripts, as a function of healthy aging and in pathology.