RESUMEN
Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases, or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of miniature excitatory synaptic currents (mEPSCs) in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin dependent whereas that caused by P301L 4R tau is dynamin independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.Significance statement Frontotemporal dementia is the third most common form of dementia caused by neurodegeneration with diverse clinical presentations. Here, we report distinct cellular mechanisms that may explain some of the similarities and differences between diverse forms of frontotemporal dementia. Tau proteins are composed of six isoforms. We found that although all isoforms can cause neural deficits, each isoform may impair the structures and functions of neurons with different temporal dynamics or through different mechanisms. The mechanistic studies of isoform-specific tau-mediated synaptic impairments reported here will add valuable information to the current molecular and cellular framework, by which diverse tau isoforms cause brain deficits in frontotemporal dementia and other neurodegenerative diseases including Alzheimer's diseases, Lewy body dementia, and chronic traumatic encephalopathy.