活性半胱天冬酶-6(aCasp-6)的tau截短(tr-tau)产生可能有毒的tau片段。然而,aCasp-6,不同形式的tr-tau和人大脑中过度磷酸化tau(p-tau)积累与阿尔茨海默病(AD)和其他tau病之间的关系仍不清楚。
我们产生了针对aCasp-6靶向的tr-tau位点(D402和D13)的两种新表位单克隆抗体。然后,我们使用五重免疫荧光来量化aCasp-6,tr-tau,p-tau及其在健康对照中的共存,AD和原发性tau蛋白病变。
在AD和Pick病(PiD)中,Casp-6激活最强,但在4重复(4R)tau蛋白病变中几乎不存在。在神经元中,AD和PiD中的tr-tau负荷比4Rtau病变中的更丰富,并且当通过p-tau病理学正常化时,tr-tau负荷不成比例地高。在4Rtau蛋白病中检测到少量的Tr-tau星形胶质细胞病。出乎意料的是,AD和PiD中约有一半的tr-tau阳性神经元缺乏p-tau聚集体,我们使用几种p-tau抗体证实了这一发现。
早期调节aCasp-6以减少tr-tau病理是AD和PiD的有希望的治疗策略,但不太可能使4Rtau蛋白病变受益。缺乏p-tau的大量tr-tau阳性神经元表明,使用常规p-tau抗体时,许多对tau病理的脆弱神经元未被检测到。针对tr-tau病理学的治疗策略对于调节AD中tau异常的程度可能是必要的。AD和PiD中tr-tau的不成比例的较高负担支持开发针对tr-tau的生物流体生物标志物以检测AD和PiD并在患者水平上将其与4Rtau蛋白病区分开。
Tau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer\'s disease (AD) and other tauopathies remains unclear.
We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies.
Casp-6 activation was strongest in AD and Pick\'s disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.
Early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.