A soluble tau fragment generated by caspase-2 is associated with dementia in Lewy body disease

Lewy body diseases are neurodegenerative disorders characterized by Lewy bodies in the brain. Lewy body dementia (LBD) refers to two forms of Lewy body disease: Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB). Tau is a cytoskeletal protein found in neurofibrillary tangles, but not Lewy bodies. The gene encoding tau, MAPT, is a well-established genetic risk factor for LBD; odds ratios of the H1:H2 MAPT haplotypes have been reported in the range of 2 to 4. Despite this genetic association, the mechanism by which tau contributes to dementia is unclear. Recently, a soluble form of tau, Δtau314, which is generated when caspase-2 (Casp2) cleaves tau at Asp314, was reported to be associated with impaired cognition in mice modeling frontotemporal dementia, and with mild cognitive impairment and Alzheimer’s disease (AD) in humans. To investigate whether Δtau314 is associated with dementia in Lewy body disease, we compared Δtau314 levels in aqueous extracts from the superior temporal gyrus of pathologically confirmed LBD (n = 21) and non-dementia Parkinson’s disease (PD) (n = 12). We excluded subjects with AD or microvascular pathology, which could mask potential associations of Δtau314 with LBD.