Tau Exon 10 Inclusion by PrPC through Downregulating GSK3β Activity

Abstract

Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrPC expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrPC levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrPC in this phenomenon. Our results indicate that PrPC plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer’s disease inPrnpmutant mice and in the P301S transgenic tauopathy mice model

“…Relevantly our data demonstrate a decrease of ptau in the absence of Aβ deposits, similarly, as happens in the above-cited manuscript with Aβ presence. Although differences in genes affected by the absence of PrP C have been described in several manuscripts with differences in the genetic background (i.e, [14, 28, 103], we previously reported that ZH3 Prnp 0/0 mice showed decreased levels of tau and increased 3R/4Rtau ratio vs wild-type mice [82]. In addition, changes in ptau and levels of tau were described during the development of FVB/N Prnp 0/0 mice vs wild-type [14].…”

miR-519a-3p, found to regulate cellular prion protein during Alzheimer’s disease pathogenesis, as a biomarker of asymptomatic stages

“…In the present study, we investigated two main issues concerning the role of miR-519a-3p in AD. On the one hand, there is its possible involvement in reducing PrP C expression levels in the evolution of the disease (Vergara, Ordonez-Gutierrez et al 2015; Lidon, Llao-Hierro et al 2021). In fact, the role of PrP C in AD and other NDDs is still a matter of debate, as some argue for its neuroprotective function while others point to it as an enhancer of the neurotoxicity associated with NDD (discussed in (Gavin, Lidon et al 2020)).…”

GSK3: A potential target and pending issues for treatment of Alzheimer's disease

“…Prion protein PrPC serves as an upstream regulator that inhibits GSK3β activation. 176 Furthermore, interferon‐gamma (IFN‐γ) initiates cellular immunity and triggers tau hyperphosphorylation via GSK3β signaling. 177 …”

“…It has also been reported that GSK3β affects the proportions of different isoforms of tau mRNA through alternative splicing. Prion protein PrPC serves as an upstream regulator that inhibits GSK3β activation 176 . Furthermore, interferon‐gamma (IFN‐γ) initiates cellular immunity and triggers tau hyperphosphorylation via GSK3β signaling 177 …”