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

Abstract

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.Using a Δtau314-specific ELISA, we found ~ 2-fold higher levels of Δtau314 in LBD relative to PD (p = 0.009). Additionally, we found ~40% lower levels of soluble total tau and the neuronal marker β-III-tubulin in LBD. These results suggest that in LBD, there is substantial neuron loss or axonal degeneration in the neocortex but disproportionately high levels of Δtau314 in the surviving neurons.Our results indicate an association between Δtau314 and dementia in Lewy body disease. Cleavage of tau by Casp2 promotes the mislocalization of tau to dendritic spines leading to a reduction in postsynaptic AMPA receptors and excitatory neurotransmission, which suggests a mechanism of the synaptic dysfunction underlying cognitive impairment in LBD. These findings support the potential of Casp2 as a novel drug target for treating LBD.

Keywords: Caspase-2; Dementia; Lewy body; Parkinson’s; Tau.

Fig. 1

∆tau314 and caspase-2 levels are higher in LBD than PD. a-c Quantification of Δtau314 and T-tau in aqueous extracts from the superior temporal gyrus. a ∆tau314 is higher in LBD than PD. b T-tau is lower in LBD than PD. c The ∆tau314: T-tau ratio is higher in LBD than PD. d Representative western blots of Casp2 and GAPDH in aqueous extracts. e Quantification of Casp2 normalized to GAPDH. Casp2 levels are higher in LBD than PD. Data were analyzed using Mann-Whitney tests. Bars indicate the medians and interquartile ranges

Fig. 2

Levels of β-III-tubulin are lower in LBD than PD. a Representative western blots of β-III-tubulin and GAPDH in aqueous extracts. b No significant difference in GAPDH levels between LBD and PD. GAPDH was used as a loading control. c Quantification of β-III-tubulin normalized to GAPDH. Normalized β-III-tubulin levels are lower in LBD than PD. d T-tau normalized to normalized tubulin (β-III: GAPDH). No difference in normalized T-tau levels. e ∆tau314 normalized to normalized β-III-tubulin are higher in LBD than PD. Data were analyzed using Mann-Whitney tests. Bars indicate medians and interquartile ranges

Fig. 3

∆tau314 and ∆tau314: T-tau ratio levels in APOE ε4 carriers and non-carriers. a, b ∆tau314 and the ∆tau314: T-tau ratio in APOE ε4 carriers versus non-carriers in only patients with LBD. c, d ∆tau314 and the ∆tau314: T-tau ratio in APOE ε4 carriers versus non-carriers in subjects with Lewy body disease (LBD and PD subjects combined). The ∆tau314: T-tau ratio is higher, and ∆tau314 trends higher, in APOE ε4 carriers. e, f Δtau314 and ∆tau314: T-tau ratio APOE ε4 non-carriers. ∆tau314 and the ∆tau314: T-tau ratio are higher in LBD. Data were analyzed using Mann-Whitney tests. Bars indicate medians and interquartile ranges

Fig. 4

T-tau and β-III-tubulin levels in APOE ε4 carriers and non-carriers. a, b T-tau and β-III-tubulin levels in APOE ε4 carriers versus non-carriers in only patients with LBD. c, d T-tau and β-III-tubulin in APOE ε4 carriers versus non-carriers in subjects with Lewy body disease (LBD and PD subjects combined). T-tau and β-III-tubulin are lower in APOE ε4 carriers. e, f T-tau and β-III-tubulin in APOE ε4 non-carriers. T-tau and β-III-tubulin are lower in LBD. Data were analyzed using Mann-Whitney tests. Bars indicate medians and interquartile ranges

Fig. 5

ROC analyses of ∆tau314, ∆tau314: T-tau, Lewy body staging, and neurofibrillary tangle staging in LBD versus PD. ROC curve analysis of a ∆tau314, b ∆tau314: T-tau, c Lewy body (LB) staging, and d neurofibrillary tangle (NFT) staging (using Braak criteria). The predictive value for dementia of ∆tau314, ∆tau314: T-tau and Lewy body staging are comparable, and superior to NFT staging. Dotted line is the line of identity (AUC = 0.5)