The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

Abstract

Disturbed neuronal cholesterol homeostasis has been observed in Alzheimer disease (AD) and contributes to the pathogenesis of AD. As the master switch of cholesterol biosynthesis, the sterol regulatory element-binding protein 2 (SREBP-2) translocates to the nucleus after cleavage/activation, but its expression and activation have not been studied in AD which is the focus of the current study. We found both a significant decrease in the nuclear translocation of N-terminal SREBP-2 accompanied by a significant accumulation of C-terminal SREBP-2 in NFT-containing pyramidal neurons in AD. N-terminal-SREBP-2 is also found in dystrophic neurites around plaques in AD brain. Western blot confirmed a significantly reduced nuclear translocation of mature SREBP-2 (mSREBP-2) in AD brain. Interestingly, reduced nuclear mSREBP-2 was only found in animal models of tauopathies such as 3XTg AD mice and P301L Tau Tg mice but not in CRND8 APP transgenic mice, suggesting that tau alterations likely are involved in the changes of mSREBP-2 distribution and activation in AD. Altogether, our study demonstrated disturbed SREBP-2 signaling in AD and related models, and proved for the first time that tau alterations contribute to disturbed cholesterol homeostasis in AD likely through modulation of nuclear mSREBP-2 translocation.

Alzheimer’s Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α

“…This hypothesis is sustained by recent reports showing that genetic polymorphisms in SREBF genes encoding sterol regulatory element-binding proteins (SREBPs), transcription factors activating lipid metabolism-related genes involved in cholesterol and fatty acids biosynthesis [42,43], were associated with an increased risk of schizophrenia and LOAD [44][45][46]. Disturbances in the signaling and expression of SREBPs were indeed reported in LOAD cases and, in a rare case of EOAD, harboring a microduplication in the locus of APP gene [47,48].…”

Key Disease Mechanisms Linked to Alzheimer’s Disease in the Entorhinal Cortex

“…Increased expression of SREBF2 levels measured in the frontal cortex is positively correlated with tau and Aβ levels in AD brains but inversely correlated with time of death [80]. Increased tau levels are also correlated with disruption of SREBF2 signaling, leading to further neurodegeneration [81]. Overexpression of SREBF2 exacerbates Aβ accumulation in neuronal cells and increases synaptotoxicity and memory deficits [82].…”

Gut microbiota modulation in Alzheimer's disease: Focus on lipid metabolism

“…Interestingly, SREBPs regulate 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), which is the rate-limiting enzyme in cholesterol biosynthesis, but the exact mechanism of action of cholesterol lowering drugs and their implication in reducing susceptibility to AD are not exactly defined [11,23,24]. Additionally, LXRs represent attractive therapeutic opportunities in AD because their activation controls the expression of genes involved in cholesterol uptake, efflux, transport, and excretion in multiple tissues, counteracts inflammation by modulating innate and adaptive immune responses, positively impacts glucose homeostasis, and decreases Ab production by modulating amyloid precursor protein processing [25,26].…”