N. Bud Grossman Center for Memory Research and Care, University of Minnesota, 2101 6th Street SE, Minneapolis, 55455, USA.
Department of Neurology, University of Minnesota, Minneapolis, USA.
Acta Neuropathol Commun. 2019 Jul 30;7(1):124. doi: 10.1186/s40478-019-0765-8.
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.
路易体病是一种神经退行性疾病，其特征是大脑中存在路易体。路易体痴呆症（LBD）是指两种路易体疾病：伴痴呆的帕金森病（PDD）和路易体痴呆（DLB）。tau 是一种细胞骨架蛋白，存在于神经原纤维缠结中，但不存在于路易体中。编码 tau 的基因 MAPT 是 LBD 的一个明确的遗传风险因素；H1:H2 MAPT 单倍型的优势比已报道在 2 到 4 之间。尽管存在这种遗传关联，但 tau 导致痴呆的机制尚不清楚。最近，一种可溶性 tau 形式 Δtau314，当半胱天冬酶-2（Casp2）在天冬氨酸 314 处切割 tau 时生成，据报道与模拟额颞叶痴呆的小鼠认知障碍有关，并与人类轻度认知障碍和阿尔茨海默病（AD）有关。为了研究 Δtau314 是否与路易体病中的痴呆有关，我们比较了经病理证实的 LBD（n=21）和非痴呆性帕金森病（PD）（n=12）的水提取液中 Δtau314 的水平。我们排除了 AD 或微血管病理学患者，因为这可能会掩盖 Δtau314 与 LBD 之间的潜在关联。使用 Δtau314 特异性 ELISA，我们发现 LBD 中 Δtau314 的水平比 PD 高约 2 倍（p=0.009）。此外，我们发现 LBD 中可溶性总 tau 和神经元标志物 β-III-微管蛋白的水平低约 40%。这些结果表明，在 LBD 中，新皮质中存在大量神经元丢失或轴突变性，但存活神经元中 Δtau314 的水平异常升高。我们的结果表明，在路易体病中，Δtau314 与痴呆有关。Casp2 对 tau 的切割促进 tau 向树突棘的错误定位，导致突触后 AMPA 受体减少和兴奋性神经传递减少，这表明 LBD 认知障碍下突触功能障碍的机制。这些发现支持 Casp2 作为治疗 LBD 的新型药物靶点的潜力。
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