Expression of tau mRNA and soluble tau isoforms in affected and non‐affected brain areas in Alzheimer's disease

Abstract

In Alzheimer's disease (AD), selective expression of tau isoforms might underlie the susceptibility of different brain areas to develop neurofibrillary tangles and this pattern might change in the disease. In this study, we have analyzed in control subjects and in sporadic AD patients the pattern of expression of tau mRNA and tau proteins in areas unaffected (cerebellar cortex, white matter), moderately affected (occipital striate cortex, thalamus, caudate nucleus, and putamen) or strongly affected by neurofibrillary tangles (temporal and frontal associative cortex). After RT-PCR amplification, five products corresponding to the tau mRNAs containing exons 2 and 3, exon 2, without exons 2 or 3, with exon 10 and without exon 10 were identified. In control subjects, these five PCR products were present in all areas except in white matter, where transcripts with exons 2 or exons 2 and 3 were not identified. In AD patients, the same pattern of transcripts was observed in different areas, regardless of the presence of neurofibrillary lesions. After dephosphorylation of soluble tau proteins, the six tau isoforms were identified in the same areas by immunoblotting, including in the white matter, suggesting that most tau isoforms with exons 2 and 3 are transported along axons. The relative expression of 0N3R isoforms was higher in the temporal cortex than in the cerebellar cortex, both in control and AD subjects. The qualitative pattern of expression was identical in subjects with or without an APOE4 allele. Our results suggest that splicing regulation of the tau gene and the relative expression of tau isoforms are not significantly changed in sporadic cases of the disease, although differential expression of tau isoforms in temporal cortex might underlie this brain area susceptibility to neurofibrillary tangles formation.

Cyclic AMP-dependent Protein Kinase Regulates the Alternative Splicing of Tau Exon 10

“…The finding of increased 3R-tau level in AD brain is inconsistent with previous studies, which showed either an increase in 4R-tau expression in brain regions affected by sporadic AD (15,45) or no change in tau isoforms in AD brain (13,46). Most of these studies detected mRNA levels of 3R-tau and 4R-tau.…”

Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis

“…The increase of total tau in AD brains (59,60) is not likely caused by up-regulated transcription of tau gene but by an upregulated translation of tau mRNA because tau mRNA copy number is not changed in sporadic AD brains (61,62), and tau mRNA has 5Ј toplike structure that is preferentially regulated by the mTorC1-S6K pathway (36,42). Inhibition of mTor with rapamycin induces a decrease in the level of total tau both in vitro and in vivo (36,43,51).…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…63,64,212 No difference in the ratio of four-and three-repeat isoforms was found in total postmortem AD brain tau, but a roughly 1.5-fold excess of four-repeat tau has been reported in the temporal cortices of AD brains. 207,213,214 Four-repeat tau binds microtubules with a higher affinity than three-repeat tau, and an isoform imbalance in favor of four-repeat isoforms might impair kinesin-dependent anterograde traffic, because tau and kinesins bind to the microtubule surface in a competitive fashion. 28,30,146 Shifting the tau isoform ratio from fourrepeat to three-repeat isoforms by alternative splicing was therefore proposed as a therapeutic option in tauopathies.…”