Imbalanced cholesterol metabolism in Alzheimer's disease

Zhao, Xinyang; Peng, Juan; Wu, Qi; Zhong, Ren; Pan, Lihong; Tang, Zhi‐Han; Jiang, Zhi‐Sheng; Wang, Guixue; Liu, Lu‐Shan

doi:10.1016/j.cca.2016.02.024

Cited by 111 publications

(93 citation statements)

References 54 publications

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“…In the periphery, cholesterol is produced in the liver or obtained through diet. Mounting epidemiological, clinical, and animal research indicates that high plasma lipid levels (i.e., hypercholesterolemia) act as a risk factor for AD [51]. Hypercholesterolemia is thought to possibly damage the BBB, resulting in pathological cholesterol metabolism in the brain [51].…”

Section: Discussionmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

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Section: Discussionmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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“…Moreover, compared with the rabbits with a normal diet, the rabbits fed a 2% high cholesterol diet might change the permeability of the blood‐brain barrier (BBB) . The dysfunction of the BBB might allow more changed molecules entering to the microenvironment of the central nervous system, accelerating the pathological progress including Aβ deposition, NFTs, neuronal apoptosis, and microglial activation . Hyperlipidemia might aggravate the deposition of Aβ, impair the cholinergic system and change the permeability of BBB, which could damage cerebral vessels and neurons …”

Section: Metabolic Damage Modelsmentioning

confidence: 99%

Advance of sporadic Alzheimer's disease animal models

Zhang

Chen

Mak

et al. 2019

Medicinal Research Reviews

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Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease. In the past decades, numbers of promising drug candidates showed significant anti‐AD effects in preclinical studies but failed in clinical trials. One of the major reasons might be the limitation of appropriate animal models for evaluating anti‐AD drugs. More than 95% of AD cases are sporadic AD (sAD). However, the anti‐AD drug candidates were mainly tested in the familial AD (fAD) animal models. The diversity between the sAD and fAD might lead to a high failure rate during the development of anti‐AD drugs. Therefore, an ideal sAD animal model is urgently needed for the development of anti‐AD drugs. Here, we summarized the available sAD animal models, including their methodology, pathologic features, and potential underlying mechanisms. The limitations of these sAD animal models and future trends in the field were also discussed.

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“…Results obtained in recent years suggest that the Aβ peptides are not the only participants in the disease mechanism(s), even though they appear to be the major culprits in the processes leading to neural damage and AD. It is still not known how or in which form the Aβ peptides induce death of neuronal cells, nor is the relative importance of other proposed contributing effects fully understood …”

Section: Amyloid Structuresmentioning

confidence: 99%

“…It is still not known how or in which form the Ab peptides induce death of neuronal cells, nor is the relative importance of other proposed contributing effects fully understood. [16] Further physiological aspects that may be important for AD are peptide degradation mechanisms, [17] induced immune responses, [3] and cholesterol metabolism. [16] The inflammatory conditions associated with AD pathogenesis were originally considered a secondary effect, but recent work has suggested that inflammation may be an important driving force behind AD.…”

Section: The Amyloid Cascade Hypothesismentioning

confidence: 99%

See 1 more Smart Citation

The Amyloid‐β Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ions

Wallin

Luo

Jarvet

et al. 2016

Israel Journal of Chemistry

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This review describes interactions between the amyloid‐β peptide (Aβ) involved in Alzheimer's disease (AD) and endogenous metal ions and proteins, with an emphasis on future potential drug therapies and targets. AD is characterised by loss of neurons, memory, and cognitive functions, and by formation of cerebral senile plaque deposits. These plaques consist mainly of aggregated Aβ peptides. AD pathology includes a) on the molecular level imbalanced concentrations of Aβ peptides and metal ions, and formation of amyloid structures, and b) on the physiological level a combination of inflammatory responses and oxidative stress effects causing neuronal death. Interestingly, certain blood proteins and metal ions can affect the Aβ amyloid aggregation process. These interactions are the topics of the present review. A deeper understanding of these interactions could facilitate new therapeutic strategies against AD. Previous therapeutic approaches and trials are also briefly described.

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Imbalanced cholesterol metabolism in Alzheimer's disease

Cited by 111 publications

References 54 publications

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Advance of sporadic Alzheimer's disease animal models

The Amyloid‐β Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ions

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