부산대학교 도서관

Neurofibrillary lesions composed of tau protein aggregates are defining hallmarks of Alzheimer's Disease. Despite tau filaments appearing to spread between networked brain regions in a prion-like manner, certain areas including cerebellum resist trans-synaptic spread of tauopathy and degeneration of their constituent neuronal cell bodies. To identify molecular correlates of resistance, we derived and implemented a ratio of ratios approach for disaggregating gene expression data on the basis of regional vulnerability to tauopathic neurodegeneration. When applied to vulnerable pre-frontal cortex as an internal reference for resistant cerebellum, the approach segregated adaptive changes in expression into two components. The first was enriched for neuron-derived transcripts associated with proteostasis including specific members of the molecular chaperone family and was unique to resistant cerebellum. When produced as purified proteins, each of the identified chaperones depressed aggregation of 2N4R tau in vitro at sub-stoichiometric concentrations, consistent with the expression polarity deduced from ratio of ratios testing. In contrast, the second component enriched for glia- and microglia-derived transcripts associated with neuroinflammation, segregating these pathways from susceptibility to tauopathy. These data support the utility of ratio of ratios testing for establishing the polarity of gene expression changes with respect to selective vulnerability. The approach has the potential to identify new targets for drug discovery predicated on their ability to promote resistance to disease in vulnerable neuron populations. Author summary: Alzheimer's disease (AD) is defined in part by the appearance of intraneuronal aggregates composed of tau protein. Because their spread through the brain correlates with cognitive decline and neurodegeneration, tau lesions serve as markers for staging disease and for recognizing nerve cell populations differentially vulnerable or resistant to AD pathogenesis. Here we compared a resistant to a vulnerable region of human brain to identify associated molecular signatures and their relationship to risk factors deduced through large-scale human genetics studies. We found that expression of genes associated with protection against intracellular protein misfolding and aggregation accompanied resistance, and that the magnitude of change correlated directly with tau burden appearing in connected brain regions. Resistance also was accompanied by expression changes in two validated AD risk genes that reproduced the directionality reported through genetic analysis. These data support the use of selective vulnerability for interrogating the directionality of gene expression changes in AD and for identifying candidate mediators of resistance to tau pathology. [ABSTRACT FROM AUTHOR]