Abstract
Alzheimer´s disease (AD) is a progressive neurodegenerative disorder of complex etiology, while Down syndrome (DS) is considered a genetically determined form of AD. Alterations in cholesterol homeostasis have been linked to AD although the role in this association is not well understood. Increased expression of STARD1 and NPC1, which are involved in intracellular cholesterol trafficking, has been reported in experimental AD models but not in patients with AD. Here we analyzed endolysosomal/mitochondrial cholesterol homeostasis, expression of NPC1 and STARD1 and correlation with pathological markers of AD in cortex and hippocampus from post-mortem brains from patients with AD and DS. NPC1 expression was observed in hippocampus from patients with AD and DS. Moreover, STARD1 expression increased in hippocampus and cortex from patients with AD and DS, respectively, and its immunoreactivity discriminated controls from AD or DS with a better accuracy than Aβ42. Hippocampal areas stained with the recombinant GST-PFO probe showed increased mitochondrial cholesterol within astrocytes of brains from patients with AD and DS-brains compared to controls. Lysosomal cholesterol accumulation within hippocampal astrocytes was higher in DS than in AD. These data revealed increased intracellular cholesterol loading in hippocampus from patient with AD and DS and suggest that STARD1 could be a potential pre-clinical marker associated with early stages of AD pathology.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of complex etiology and the most common form of dementia, which comprises early-onset Alzheimers disease (AD) (EOAD, ~5% of patients) and late-onset AD (LOAD, 95% of patients)
While the expression at mRNA or protein levels of STARD4, INSIG-1 and mature SREBP2 seems to be similar between AD, Down syndrome (DS) and control samples (Figure 1), cortex from patients with DS exhibited a significant overexpression of transcripts for the mitochondrial carrier STARD1 (Figure 1A), which translated at the protein levels (Figure 1B)
Cortex from AD-brains exhibited a small but significant increase in the Niemann Pick type C1 protein (NPC1) protein expression compared to control samples and a trend for increased STARD1 protein levels (Figure 1B). These findings indicate that cortex from patients with DS and AD exhibit increased expression of steroidogenic acute regulatory protein (StARD1) and NPC1, respectively
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of complex etiology and the most common form of dementia, which comprises early-onset AD (EOAD, ~5% of patients) and late-onset AD (LOAD, 95% of patients). While alterations in cholesterol homeostasis have been linked to AD the role for this association is controversial. There has been evidence indicating that either increased or decreased total brain cholesterol levels are associated with AD-pathogenesis [2]. Whether intracellular cholesterol pools (e.g. www.aging-us.com endolysosomes and mitochondria) rather than total cholesterol levels are more relevant for AD pathology remains to be established. Hippocampus and frontal cortex of patients with AD and AD-Tg mice have been shown to exhibit increased expression of the lysosomal cholesterol transporter NPC1 [3], while increased steroidogenic acute regulatory protein (STARD1) expression, which regulates the mitochondrial cholesterol trafficking [4], has been reported in pyramidal hippocampal neurons of patients with AD [5]. The intracellular cholesterol homeostasis in human AD has not been explored
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