Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer's disease
Introduction
Alzheimer's disease (AD) is the most common form of dementia. It is characterized by deposition in the brain of amyloid plaques, mainly constituted of amyloid β (Aβ) peptide and dystrophic neurites rich in phosphorylated tau. The strongest known risk factor influencing the incidence of sporadic AD is the ApoE genotype, where homozygosity for ApoE4 increases the risk of developing AD 12-fold [1]. Elevated midlife serum cholesterol has been associated with risk of AD later in life [2], and it has been observed that subjects treated with statins have a significantly decreased prevalence of AD [3], [4]. However, conflicting data regarding statin treatment in relation to AD have been published [5]. Aβ is produced by sequential cleavage of the amyloid precursor protein (APP) by β-secretase followed by γ-secretase. The fact that APP, β-, and γ-secretases are localized in cholesterol-rich lipid rafts, suggests that alterations in cholesterol homeostasis may affect the development of AD via modulation of Aβ production and accumulation [6]. Elevated cholesterol levels increase Aβ levels in cellular and animal models [7]. Cholesterol homeostasis and Aβ are also linked via the ATP-binding cassette A1 and A7 (ABCA1 and ABCA7) membrane transporters, where increased ABCA1 or ABCA7 expression stimulates cholesterol efflux from lipid rafts and decreases Aβ secretion [8], [9], [10], [11], [12], [13].
It has been shown that neurons of AD patients contain enlarged endosomes and increased numbers of lysosomes and are characterized by an enhanced gene expression and synthesis of lysosomal enzymes [14], [15], [16]. Interestingly, components of the γ-secretase complex such as presenilin-1 and nicastrin have been detected in the lysosomal membrane [17]. β-Secretase has also been observed in the endosomal/lysosomal system [18] and has an acidic pH optimum [19].
Cholesterol is delivered to lysosomes subsequent to receptor-mediated endocytosis of extracellular lipoprotein particles. [20]. Exit of cholesterol from lysosomes requires two proteins, lysosomal membrane-bound Niemann-Pick type C1 (NPC1) and lysosomal soluble NPC2. NPC disease is an inherited neurodegenerative lipid storage disorder. Mutations in the NPC genes lead to the retention of cholesterol and other lipids in late endosomes and lysosomes [21]. Clinical and biochemical studies suggest that cholesterol imbalance and failure of homeostatic responses in the brain can lead to the development of both AD and NPC [6], [22]. Moreover, there are several pathological similarities between AD and NPC such as the presence of neurofibrillary tangles and taupathy, endosomal and lysosomal abnormalities, and increased Aβ generation [22], [23].
In the present study, we investigated if AD has an impact on human NPC1 expression. Our data demonstrate for the first time that NPC1 mRNA and protein expression is significantly upregulated in the AD frontal cortex and hippocampus, but not in the cerebellum when compared to healthy subjects.
Section snippets
Human brain tissues
Human brain tissues were obtained from the Australian Brain Donor Programs Prince of Wales Medical Research Institute Tissue Resource Centre (supported by the Australian National Health and Medical Research Council, NHMRC) and the NSW Tissue Resource Centre (supported by The University of Sydney, NHMRC, Schizophrenia Research Institute, National Institute of Alcohol Abuse and Alcoholism, and NSW Department of Health). Ethics approval was from the University of New South Wales Human Research
NPC1 expression in human brain
To investigate the potential impact of AD on NPC1 expression, we measured NPC1 mRNA and protein expression in human brain. NPC1 mRNA was increased significantly in the frontal cortex and in the CA1 field of the hippocampus in the AD cases. This increase in NPC1 was not detected in the cerebellar cortex (a brain region that is relatively spared in AD; Fig. 1A). Analysis of NPC1 protein levels by Western blotting confirmed that NPC1 was selectively upregulated in AD in the frontal cortex and CA1
Discussion
Although AD and NPC disease are distinct neuropathological disorders, certain commonalities involving lysosomal changes, altered cholesterol homeostasis, and Aβ generation prompted us to investigate if changes in NPC1 expression occur in the AD brain. Our results demonstrate for the first time that NPC1 mRNA and protein levels are significantly upregulated in the frontal cortex and in the CA1 field of the hippocampus in AD cases compared to controls. This upregulation appears to be associated
Acknowledgments
This study was supported by a fellowship from the Swedish Research Council and grants from the foundations of Nilsson, Engkvist and Wiberg (KK) and project grant 510148 from the Australian National Health and Medical Research Council (BG). We are very grateful to Assoc Prof Andrew Hill for provision of the CHO-APP cell line and to Prof Colin Masters and Dr Qiao-Xin Li for providing WO2 antibody. Human brain tissues were obtained from the Australian Brain Donor Programs Prince of Wales Medical
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Cholesterol homeostasis: Researching a dialogue between the brain and peripheral tissues
2021, Pharmacological ResearchThe lysosomal storage disease continuum with ageing-related neurodegenerative disease
2016, Ageing Research ReviewsCitation Excerpt :Interestingly, tau deletion has been shown to exacerbate NPC phenotypes (Pacheco et al., 2009), suggesting an interaction between the two proteins, and overexpression of APP in the absence of NPC1 leads to further defects in the clearance of amyloid-β and the accumulation of APP-CTFs (Maulik et al., 2015). These findings, suggesting a link between NPC disease and AD, are supported by the observation that levels of the NPC1 protein are elevated in the hippocampus and cortex, but not the cerebellum (which is spared), of post-mortem AD patients (Kagedal et al., 2010). This process may not just be a result of the increased lysosomal biogenesis in AD as there is evidence of upregulation of NPC1 levels as a result of deficient endolysosomal cholesterol transport (Puri et al., 1999) or in response to altered sterol metabolism (Gevry et al., 2008).
Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease
2014, Neurobiology of DiseaseCitation Excerpt :We recently found increased CSF levels of six endosomal and lysosomal proteins (EEA1, LAMP-1, LAMP-2, LC3, Rab3, and Rab7) in AD patients compared to controls, and most of these (with the exception of EEA1) appeared to be specifically increased in AD, rather than general markers of neurodegeneration (Armstrong et al., 2014). In contrast to NPC1 gene downregulation observed in MCI/AD CA1 neurons in post mortem brains by Ginsberg et al. (2010), two additional reports described its increased mRNA and protein levels in both AD human brains and AD transgenic mouse models (Kågedal et al., 2010; Yao et al., 2012). Kågedal et al. (2010) analyzed mRNA/protein levels of NPC1 in different brain regions of AD patients and APP/PS1-tg mice (APPsw/Ps1∆E9) and revealed, in both models, a significantly increased NPC1 mRNA/protein expression in the hippocampus and frontal cortex, the two most affected brain areas in AD.
Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin
2014, Journal of Lipid ResearchNPC1, intracellular cholesterol trafficking and atherosclerosis
2014, Clinica Chimica ActaCitation Excerpt :Our recent investigation has demonstrated that oxidized low-density lipoprotein (oxLDL) can enhance the expression of NPC1 mRNA and protein in macrophages, and the mechanisms are associated with the extracellular signal-regulated kinase 1/2 (ERK1/2)/cyclooxygenase-2 (COX-2)/peroxisome proliferator-activated receptor α (PPARα) pathway [57]. It is suggested that NPC1 expression is upregulated at both the mRNA and protein levels in the hippocampus and frontal cortex of Alzheimer's disease patients as compared to control individuals [58]. Bambace and co-workers observed that NPC1 mRNA is significantly elevated in the subcutaneous and omental white adipose tissues of obese individuals, and is reduced by weight loss [59].
A case report of 'variant' biochemical phenotype of Niemann-Pick C disease and a discussion of therapeutic options
2013, Neurologia i Neurochirurgia Polska