Association of Polymorphisms of the Tissue Inhibitors of Metalloproteinases-1 and -2 with Alzheimer’s Disease in Taiwan

Background: Alzheimer’s disease (AD) leads to progressive neuronal loss and cognitive and behavioral decline in the aging population. Matrix metalloproteinases (MMPs) and associated tissue inhibitors of metalloproteinases (TIMPs) are involved in remodeling the extracellular matrix. Amyloid beta-42 interrupts the integrity of the neurovascular unit and induces a toxic reaction affecting neurons. Objective: This study investigated the relationships among genetic variants of the MMP-2, MMP-9, TIMP-1, and TIMP-2 genes and AD. Methods: Two hundred and thirteen probable AD patients and 315 control participants of the Tai- wan population were recruited for primary investigations, and we used the data of 763 participants from the Taiwan Biobank (TWB), as controls, for validation. Multivariable logistic regression was performed with adjustments for age, sex, hypertension, diabetes mellitus (DM), and alcohol con- sumption. The associations between the genotypes and allele frequencies and the SNP-associated AD hereditary models were analyzed using the SNPassoc package for R. We performed a permuta- tion test with 1,000 replicates for the empirical estimates. Results: A total of 213 probable AD patients and 315 control participants were recruited. The fre- quency of the A alleles in rs7503726 (G > A) in TIMP-2 was lower in the AD patients (p < 0.01). The frequencies of the TIMP-2 rs7503726 G/A and A/A genotypes were also significantly lower in the AD patients (p = 0.02) than in the controls and TWB. The TIMP-2 rs7503726 AA genotype was associated with a protective effect of AD in additive and recessive hereditary models (OR = 0.54, 95% CI: 0.32 – 0.92, p = 0.02; OR = 0.68, 95% CI: 0.50 – 0.92, p = 0.01, respectively). Conclusion: The TIMP-2 rs7503726 AA genotype was inversely correlated with AD susceptibili- ty, and the presence of minor alleles of rs7503726 (A allele) have protective effects against AD.

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Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury

Pharmaceuticals ◽

10.3390/ph13110379 ◽

2020 ◽

Vol 13 (11) ◽

pp. 379

Author(s):

Michał Wiciński ◽

Eryk Wódkiewicz ◽

Karol Górski ◽

Maciej Walczak ◽

Bartosz Malinowski

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Damage ◽

Neurovascular Unit ◽

Neuronal Loss ◽

Impact Risk ◽

Sglt2 Inhibition ◽

The Central Nervous System ◽

Cortical Regions ◽

Endothelial Growth Factor

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer’s disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.

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Sinapic Acid Alleviates Oxidative Stress and Neuro-Inflammatory Changes in Sporadic Model of Alzheimer’s Disease in Rats

Brain Sciences ◽

10.3390/brainsci10120923 ◽

2020 ◽

Vol 10 (12) ◽

pp. 923

Author(s):

Vandna Verma ◽

Devendra Singh ◽

Reeta KH

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Sinapic Acid ◽

Neuronal Loss ◽

Protective Effects ◽

Cholinergic Dysfunction ◽

Model Of Alzheimer’S Disease ◽

Neuro Inflammation

The role of oxidative stress, neuro-inflammation and cholinergic dysfunction is already established in the development of Alzheimer’s disease (AD). Sinapic acid (SA), a hydroxylcinnamic acid derivative, has shown neuro-protective effects. The current study evaluates the neuro-protective potential of SA in intracerebroventricular streptozotocin (ICV-STZ) induced cognitive impairment in rats. Male Wistar rats were bilaterally injected with ICV-STZ. SA was administered intragastrically once daily for three weeks. Rats were divided into sham, ICV-STZ, STZ + SA (10 mg/kg), STZ + SA (20 mg/kg) and SA per se (20 mg/kg). Behavioral tests were assessed on day 0 and 21 days after STZ. Later, rats were sacrificed for biochemical parameters, pro-inflammatory cytokines, choline acetyltransferase (ChAT) expression and neuronal loss in the CA1 region of the hippocampus. The results showed that SA 20 mg/kg significantly (p < 0.05) improved cognitive impairment as assessed by Morris water maze and passive avoidance tests. SA 20 mg/kg reinstated the altered levels of GSH, MDA, TNF-α and IL-1β in the cortex and hippocampus. STZ-induced decreased expression of ChAT and neuronal loss were also significantly (p < 0.05) improved with SA. Our results showed that SA exhibits neuro-protection against ICV-STZ induced oxidative stress, neuro-inflammation, cholinergic dysfunction and neuronal loss, suggesting its potential in improving learning and memory in patients of AD.

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BMI1 is associated with CS8F amyloid-β and rates of cognitive decline in Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00906-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jun Pyo Kim ◽

Bo-Hyun Kim ◽

Paula J. Bice ◽

Sang Won Seo ◽

David A. Bennett ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Cognitive Performance ◽

Association Analysis ◽

Amyloid Β ◽

Minor Allele ◽

Protective Mechanism ◽

Protective Effects ◽

Minor Alleles

Abstract Background Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer’s disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-β. Methods We used genetic, longitudinal cognition, and cerebrospinal fluid (CSF) biomarker data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). First, we performed a gene-based association analysis of common single nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) > 5%) located within ± 20 kb of the gene boundary of BMI1, an optimal width for including potential regulatory SNPs in the 5′ and 3′ untranslated regions (UTR) of BMI1, with CSF Aβ1-42 levels. Second, we performed cross-sectional and longitudinal association analyses of SNPs in BMI1 with cognitive performance using linear and mixed-effects models. We replicated association of SNPs in BMI1 with cognitive performance in an independent cohort (N=1084), Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Results Gene-based genetic association analysis showed that BMI1 was significantly associated with CSF Aβ1-42 levels after adjusting for multiple testing using permutation (permutation-corrected p value=0.005). rs17415557 in BMI1 showed the most significant association with CSF Aβ1-42 levels. Participants with minor alleles of rs17415557 have increased CSF Aβ1-42 levels compared to those with no minor alleles. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD. Conclusions Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.

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The Associations of Plasma/Serum Carotenoids with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Journal of Alzheimer s Disease ◽

10.3233/jad-210384 ◽

2021 ◽

pp. 1-12

Author(s):

Mingyue Qu ◽

Hanxu Shi ◽

Kai Wang ◽

Xinggang Wang ◽

Nan Yu ◽

...

Keyword(s):

Systematic Review ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Meta Analysis ◽

Scoring Systems ◽

Serum Levels ◽

Epidemiological Studies ◽

Pooled Analysis ◽

Protective Effects ◽

Mean Differences

Background: Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD. Objective: Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with 95%confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots and Egger’s test. Results: Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = –0.86, 95%CI: –1.67 to –0.05, p = 0.04) and zeaxanthin (SMD = –0.59; 95%CI: –1.12 to –0.06, p = 0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95%CI: –0.68 to 0.26, p = 0.39), β-carotene (SMD = 0.04, 95%CI: –0.57 to 0.65, p = 0.9), lycopene (SMD = –0.12, 95%CI: –0.96 to 0.72, p = 0.78), and β-cryptoxanthin (SMD = –0.09, 95%CI: –0.83 to 0.65, p = 0.81) did not achieve significant differences. Conclusion: Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings.

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Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Scientific Reports ◽

10.1038/s41598-021-83872-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Boris Guennewig ◽

Julia Lim ◽

Lee Marshall ◽

Andrew N. McCorkindale ◽

Patrick J. Paasila ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rna Sequencing ◽

Neuronal Loss ◽

Brain Regions ◽

Post Mortem ◽

Tau Pathology ◽

Membrane Spanning ◽

Immune Related Genes ◽

Vesicle Secretion

AbstractTau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

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Microglia and its genetics in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205018666211105140732 ◽

2021 ◽

Vol 18 ◽

Author(s):

Xinyan Liang ◽

Haijian Wu ◽

Mark Colt ◽

Xinying Guo ◽

Brock Pluimer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Morphological Changes ◽

Association Studies ◽

Unmet Need ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Risk Genes ◽

Main Component

: Alzheimer’s Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid-beta (Aβ) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in both pathogenesis and progression. As the main innate immune cell type in central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many of AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aβ. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complexed etiology of AD and provide new insight for the unmet need of effective treatment.

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Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/617420 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Peter Wostyn ◽

Debby Van Dam ◽

Kurt Audenaert ◽

Peter Paul De Deyn

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Senile Plaques ◽

Protective Effects ◽

Caffeine Consumption ◽

Neuroprotective Effects ◽

Csf Production

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na+-K+ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

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Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

International Journal of Alzheimer s Disease ◽

10.4061/2011/920958 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Laurence Barrier ◽

Bernard Fauconneau ◽

Anastasia Noël ◽

Sabrina Ingrand

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Neuronal Death ◽

Time Course ◽

Neuronal Loss ◽

Brain Regions ◽

App Processing ◽

Ceramide Accumulation ◽

The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

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