Astrocyte and neuron brain-region and compartment-specific proteome dynamics in aging and Alzheimer’s disease

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Alzheimer’s disease (AD) is a complex age-dependent disorder. It requires multiple approaches to comprehensively understand at a molecular level in order to develop novel diagnostics and disease modifying treatments. Astrocytes and neurons coexist in the brain and both major cell types are known to contribute to AD. The cellular phase of AD is proposed to comprise feedback and feedforward signaling between diverse brain cells as a link between the initial emergence of molecular pathology (abnormal tau and Aβ) and subsequent disease manifestations. Known glial cell proteins that contribute to this cellular phase are APOE and TREM2, and are associated with significantly increased risk of AD. Moreover, known astrocyte mechanisms include reactivity, which is a complex, non-binary phenomenon with sequelae that depends on context. In the past, most disease related studies have evaluated astrocytes or neurons using assessments of physiology, markers, or with gene expression evaluations. Astrocytes and neurons have not been studied in detail together or with cell-type specific proteomic methods, as proposed here and as requested by the FOA. As a result, despite advances, we have little precise information about the proteomes of astrocytes and neurons during aging in brain areas relevant to AD or in brain regions relevant to specific and defined abnormalities such as seizure activity in AD. Our overarching hypothesis is that astrocytes and neurons display protein dynamics during normal ageing and in mouse models of AD and that these changes reflect signaling between these dominant brain cells during the cellular phase of AD pathogenesis and during aberrant seizure activity and its associated cognitive decline in AD. Aim 1 will characterize cell, brain region, and compartment (plasma membrane versus cytosol) specific proteomic methods for astrocytes and neurons. Aim 2 will determine astrocyte and neuron proteomic dynamics during normal aging in mice. Aim 3 will determine astrocyte and neuron proteomic dynamics during aberrant network activity in AD model mice. Understanding the identities and the extent of cell, brain region, and compartment-specific protein changes for the major brain cell types (astrocytes and neurons) using data-driven unbiased approaches could be foundational and catalytic with regards to new opportunities for translational and mechanistic work.