Biochemical and molecular heterogeneity of human TDP-43 proteinopathies in age-related dementias

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The brain is presence of phosphorylated deposits of the neuropathological hallmark of transactive response DNA-binding protein 43 (TDP-43) in the frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Moreover, in retrospective studies, TDP-43 proteinopathy was shown to be associated with substantial cognitive impairment that mimicked the Alzheimer's disease (AD) clinical syndrome. The co- existence of TDP-43 pathology in brains with neuropathological change of AD (ADNC) has been reported in 30-70% of AD cases, predominantly affecting predominant Recent subtype limbic and associated areas in a pattern called limbic- age-related TDP-43 encephalopathy neuropathological change (LATE-NC). studies have shown that LATE-NC is also found in individuals without ADNC, postulating a new ofTDP-43 proteinopathy designated as LATE. LATE is one of the most prevalent subsets of TDP-43 proteinopathies observed in ~30-50% of people who die beyond 85 years of age. When comparing LATE-NC with FTLD-TDP cases, recent studies have shown that besides distinct clinical manifestations, there are also differences in epidemiological, genetic, and neuroimaging features. From a neuropathological standpoint, LATE-NC and FTLD-TDP individuals share some features of TDP-43 pathology. Since phosphorylated TDP-43 was identified as the major component of ubiquitin-positive inclusions in FTLD-TDP, five distinct FTLD-TDP histopathological distribution and morphological features of TDP-43 aggregates (type between clinical symptoms, genetic forms of FTLD-TDP, and TDP-43 neuropathological subtypes have been established based on characteristic A to E) features . The association in FTLD-TDP brains have been extensively reported. Interestingly, although TDP-43 pathology in some LATE-NC cases resembles FTLD-TDP type A, a distinctive neuropathological feature related to TDP-43 proteinopathy in elderly individuals is type “Alpha” (similar to type A) or type “Beta” (co-mingling with tau tangle structures) pattern of TDP-43 immunoreactivity in the amygdala. The molecular mechanism(s) underlying the heterogeneity of the TDP-43 proteinopathies is still unknown. Such heterogeneity supports a “strain hypothesis” wherein unique pathogenic TDP-43 species (a.k.a. strains) with different conformations may play a role in such diversity. Our objective is to isolate pathogenic TDP-43 species present in FTLD-TDP and LATE-NC brains and characterize their biochemical properties and biological activities in vitro and in vivo (Aim 1). We will then generate in vitro brain-derived TDP-43 strains that recapitulate the characteristic features of their human counterparts (Aim 2). Finally, we will determine whether there are differential pathophysiological signaling pathways associated with neuropathological changes of TDP-43 pathology in the brain by performing spatial profiles between distinct TDP-43 proteinopathies transcriptomic analysis and comparing the expression (Aim 3 ).