Modulation of Tau Isoforms Imbalance Precludes Tau Pathology and Cognitive Decline in a Mouse Model of Tauopathy

Abstract

The microtubule-associated protein tau regulates myriad neuronal functions, such as microtubule dynamics, axonal transport and neurite outgrowth. Tauopathies are neurodegenerative disorders characterized by the abnormal metabolism of tau, which accumulates as insoluble neuronal deposits. The adult human brain contains equal amounts of tau isoforms with three (3R) or four (4R) repeats of microtubule-binding domains, derived from the alternative splicing of exon 10 (E10) in the tau transcript. Several tauopathies are associated with imbalances of tau isoforms, due to splicing deficits. Here, we used a trans-splicing strategy to shift the inclusion of E10 in a mouse model of tauopathy that produces abnormal excess of 3R tau. Modulating the 3R/4R ratio in the prefrontal cortex led to a significant reduction of pathological tau accumulation concomitant with improvement of neuronal firing and reduction of cognitive impairments. Our results suggest promising potential for the use of RNA reprogramming in human neurodegenerative diseases.

Transmission of tauopathy strains is independent of their isoform composition

“…While the adult WT mice only express 4R tau isoforms, the existing transgenic mice Htau 24 and MAPT KI 25 express much more 3R tau than 4R tau. Through virus injection RNA splicing could be modulated in Htau mice, but only in local brain regions that received injection 26 . The transgenic 6hTau mouse generated here is a unique mouse that express all six Htau isoforms with a nearly equal 3R and 4R ratio in many different brain regions during most of mouse lifespan.…”

The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases

“…A shift in the normal balance of tau isoforms (3R and 4R) in the human brain has been associated with abnormal neuronal firing and cognitive impairment. Modulating the tau isoform imbalance with RNA reprogramming (trans-splicing strategy) was associated with reduced accumulation of pathological tau and is therefore regarded as a promising therapeutic strategy for neurodegenerative diseases and may possess similar therapeutic value for pathology associated with p53 isoform imbalance [88]. Investigating therapeutics at the protein level, Lei at al.…”

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

“…This exacerbation of pathological tau could be resulting from differences in the extent to which we altered the isoform ratio in the model. Espindola et al (46) indeed reprogrammed 3R to 4R tau isoforms to a ratio of ∼1 to mimic the balance seen in the healthy human brain, while with our breeding strategy, 3R tau remained the predominant isoform. While a balance between the two isoforms may be critical to protect from the development of tau pathology, both 3R and 4R tau were found toxic in drosophila, with isoform-specific mechanisms of tau toxicity and phosphorylation potential (68).…”

“…This enabled the production of all experimental animals from five genotypes as littermates: Wt, mTau +/− , mTau −/− , hTau/mTau +/− , and hTau/mTau −/− . Previous studies investigating the impact of modulation of the 4R:3R tau isoform ratio on tau pathology have used either males (46) or both males and females but without testing for sex differences (47), although sex differences in disease progression have been reported in hTau mice (50). As we did not have an a priori hypothesis on sex differences in the impact of 4R tau availability on immune responses, we only used male mice for this study.…”

“…It involves the expression of all six, non-mutated, human tau isoforms, but the altered ratio of tau isoforms favoring 3R tau due to the concomitant loss of murine tau (mTau) that is predominantly 4R is thought to underlie pathological changes in this model (36). In favor of this hypothesis, restoring tau isoform imbalance to a 4R:3R ratio of ∼1 by increasing 4R tau levels was found to alleviate tau pathology and cognitive deficits in these mice (46). On the other hand, increasing 4R tau and decreasing 3R tau expression without altering total tau levels was found to worsen tau pathology and associated behavioral deficits in hTau mice (47).…”