Markers of cholesterol transport are associated with amyloid deposition in the brain

Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, USA. Electronic address: .
Neurobiology of aging (Impact Factor: 5.01). 10/2013; 35(4). DOI: 10.1016/j.neurobiolaging.2013.09.040
Source: PubMed


Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.

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    • "An association with amyloid deposition has been described for ABCA7 rs3764650 (Shulman et al., 2013), ABCA7 rs3752246 (Hughes et al., 2014), BIN1 rs744373 (Hohman et al., 2013), CR1 rs6701713 (Shulman et al., 2013), CR1 rs3818361 (Thambisetty et al., 2013), CR1 rs6656401, and CLU rs3818361 (Hohman et al., 2013). CD2AP rs9349407 has been associated with postmortem neuritic plaque burden in the advanced stages of the disease (Shulman et al., 2013), but interestingly not with PiB binding in nondemented elderly (Hughes et al., 2014). "

    Full-text · Article · Nov 2015
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    • "The hypothesis is further substantiated by findings showing direct interaction between CLU and Aβ [25], [26]. However, despite these suggestive preclinical findings, clinical data is lacking to corroborate a significant effect of CLU on Aβ burden as a major mechanism underlying the genetic link to AD [27], [28]. Healthy carriers of the CLU rs11136000 risk allele C show decreased white matter integrity [29], altered coupling between hippocampus and prefrontal cortex during memory processing [30], and significant longitudinal increases of cerebral blood flow in the hippocampus and anterior cingulate cortex [31], indicating that CLU may also participate in non-Aβ pathways that could modulate vulnerability to AD. "
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    ABSTRACT: Sporadic or late-onset Alzheimer's disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Thus, oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle characterize AD as a protein misfolding disease, with protein clearance defects through the ubiquitin-proteasome system (Hong et al., 2014; Valasani et al., 2014). There is strong evidence, also, that APP may act as a trophic factor relevant to neurite outgrowth and synaptogenesis, as well as growth and cell proliferation (Abramov et al., 2009; Jiang et al., 2013; Bukanova et al., 2014; Dawkins and Small, 2014; Hughes et al., 2014). However, future research are required to fully clarify mechanisms of APP action (Dawkins and Small, 2014). "
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    ABSTRACT: Alzheimer's disease (AD) and osteoporosis are multifactorial progressive degenerative disorders. Increasing evidence shows that osteoporosis and hip fracture are common complication observed in AD patients, although the mechanisms underlying this association remain poorly understood. Reactive oxygen species (ROS) are emerging as intracellular redox signaling molecules involved in the regulation of bone metabolism, including receptor activator of nuclear factor-κB ligand-dependent osteoclast differentiation, but they also have cytotoxic effects that include lipoperoxidation and oxidative damage to proteins and DNA. ROS generation, which is implicated in the regulation of cellular stress response mechanisms, is an integrated, highly regulated, process under control of redox sensitive genes coding for redox proteins called vitagenes. Vitagenes, encoding for proteins such as heat shock proteins (Hsps) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein, represent a systems controlling a complex network of intracellular signaling pathways relevant to life span and involved in the preservation of cellular homeostasis under stress conditions. Consistently, nutritional anti-oxidants have demonstrated their neuroprotective potential through a hormetic-dependent activation of vitagenes. The biological relevance of dose-response affects those strategies pointing to the optimal dosing to patients in the treatment of numerous diseases. Thus, the heat shock response has become an important hormetic target for novel cytoprotective strategies focusing on the pharmacological development of compounds capable of modulating stress response mechanisms. Here we discuss possible signaling mechanisms involved in the activation of vitagenes which, relevant to bone remodeling and through enhancement of cellular stress resistance provide a rationale to limit the deleterious consequences associated to homeostasis disruption with consequent impact on the aging process.
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