A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Abstract

Neurofibrillary tangles are a pathological hallmark of Alzheimer's disease, and their levels correlate with the severity of cognitive dysfunction in humans. However, experimental evidence suggests that soluble tau species cause cognitive deficits and memory impairment. Our recent study suggests that caspase-2 (Casp2)-catalyzed tau cleavage at aspartate 314 mediates synaptic dysfunction and memory impairment in mouse and cellular models of neurodegenerative disorders. Δtau314, the C-terminallytruncated cleavage products, are soluble and present in human brain. In addition, levels of Δtau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for Δtau314 proteins in cognitive deterioration. Here we show that (1) Δtau314 proteins are present in the inferior temporal gyrus of human brains; (2) Δtau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and Δtau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of Δtau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of Δtau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated Δtau314 production to cognitive deterioration.Tau is a soluble and unstructured protein, is enriched in neurons of the central nervous system (CNS), and plays an essential role in the formation and stabilization of microtubules to maintain normal neuronal structure and function 1,2 . In the human CNS, six isoforms of tau are generated by alternative splicing of exons 2, 3, or 10 of mRNA 3,4 . Tau is subjected to more than ten types of post-translational modifications (PTMs); under pathological conditions, the coordinated actions of multiple tau PTMs result in its dissociation from microtubules and intra-cellular aggregation to form neurofibrillary tangles (NFTs), a pathological hallmark of Alzheimer's disease (AD) (for review, see 5 ). As the burden of NFTs in a variety of brain regions correlate well with the severity of cognitive deficits of AD patients (for example, see 6-10 ), NFTs were assumed to be one of the major drivers of cognitive impairment. However, Gomez-Isla and colleagues observed that in the brain of individuals with AD, both the amount of neuron loss and the amount of NFTs in the disease-affected superior temporal sulcus correlate with the duration and severity of cognitive dysfunction, but the former exceeds the latter more than 7-fold. This suggests that neuronal loss, rather than NFTs, contributes directly to cognitive dysfunction in AD 11 . Further, several studies using tau transgenic mouse models have shown that synaptic function impairment and cognitive deficits

Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation

“…Intriguingly, recent reports suggest that, indeed, caspase-2-dependent generation of Δtau314 is also responsible for the cognitive deficits seen in Lewy body disease, non-dementia Parkinson's disease as well as Huntington's disease [88,89]. Strikingly, a recent study on human individuals suffering from AD found that the levels of Δtau314 correlate with cognitive impairment, and also caspase-2 protein levels were increased in these patients, confirming the findings made in mouse models [90]. In addition to cleavage of tau, caspase-2 was found to shape dendritic spines by regulating AMPA receptor internalization via proteolytic cleavage of Rictor, thus inhibiting mTORC2 signaling.…”

Cellular Biology of Tau Diversity and Pathogenic Conformers

“…This C-terminally truncated fragment of tau mis-localizes to dendritic spines and causes cognitive dysfunction in an animal model of tauopathy (51). A recent report indicates elevated levels of this fragment in cognitively impaired human kindreds (78). A 35 kDa N-terminally truncated tau fragment entailing the microtubule-binding repeat domains was reported to be present in post-mortem brains of patients diagnosed with tauopathies in which 4R isoforms predominate (79).…”

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

“…Interestingly, tau and α-syn also seem to contribute to HD pathology (Tomás-Zapico et al 2012, Fernández-Nogales et al 2014). Specific tau modifications and cleavage products associated with cognitive decline in AD were found in the brains of HD patients and suggested HD as a new tauopathy (Liu et al 2020, Fernández-Nogales et al 2014). Similarly, increased levels of α-syn were observed in plasma of patients with HD (Shalash et al 2017, Breza et al 2020).…”