Abstract
Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.
Highlights
Alzheimer’s disease (AD) is characterized by both amyloid-b (Ab) plaques and tau tangles in the brain while tau pathology in the absence of plaques occurs in a subset of frontotemporal lobar degeneration (FTLD-Tau) that includes FTDP-17 and Pick’s disease (PiD) [1]
Features of FTLD-Tau have been reproduced in transgenic mice expressing FTDP-17 mutant tau [2]: P301L tau transgenic pR5 mice are characterized by tau hyperphosphorylation, tangle formation in the amygdala and hippocampus, and memory impairment [3]
These studies were all done with total brain, while here we focused on the amygdala, a brain area with prominent tau pathology and affected early on in AD pathogenesis
Summary
Alzheimer’s disease (AD) is characterized by both amyloid-b (Ab) plaques and tau tangles in the brain while tau pathology in the absence of plaques occurs in a subset of frontotemporal lobar degeneration (FTLD-Tau) that includes FTDP-17 and Pick’s disease (PiD) [1]. To determine the consequences of tau pathology, both in animal models and human disease, we and others have applied the tools of functional genomics [4]. E.g., revealed separate and synergistic modes of Ab and tau on mitochondrial functions [5,6] while in a transcriptomic study, we identified the detoxifying enzyme glyoxalase I as a target of tau toxicity [7]. These studies were all done with total brain, while here we focused on the amygdala, a brain area with prominent tau pathology and affected early on in AD pathogenesis. Instead of using gene arrays to identify differential gene expression, we used the unbiased, though less frequently applied SAGE (Serial Analysis of Gene Expression) method [8]
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