OBJECTIVE:Recent studies have suggested that diminished Ccr5 functioning has an effect on synaptic plasticity and hippocampal memory in mouse models. CCR5-delta32, a 32-bp frameshift deletion in ...human CCR5 encoding a nonfunctional receptor, has been reported to have a protective effect against human immunodeficiency virus infection but its role as a modifier of neurodegenerative disease has been minimally explored. We investigated whether the CCR5-delta32 polymorphism could have an effect in the context of human neurodegenerative diseases.
METHODS:We examined the frequency of the CCR5-delta32 polymorphism in a large and well-characterized cohort including 1425 patients with neurodegenerative dementias and 2032 controls.
RESULTS:We did not observe a significant association between the CCR5-delta32 polymorphism and any of the neurodegenerative diseases screened in this study. However, we observed an earlier age of onset among neurodegenerative disease patients carrying the CCR5-delta32 allele.
CONCLUSIONS:Although our findings were inconclusive, the earlier age of onset observed among neurodegenerative disease patients carrying the CCR5-delta32 allele suggests that the deletion may have a detrimental effect in the context of neurodegeneration.
E-cadherin, the primary epithelial adherens junction protein, has been implicated as playing a critical role in nucleating formation of adherens junctions, tight junctions, and desmosomes. In ...addition to its role in maintaining structural tissue integrity, E-cadherin has also been suggested as an important modulator of cell signaling via interactions with its cytoplasmic binding partners, catenins, as well as with growth factor receptors. Therefore, we proposed that loss of E-cadherin from the developing mouse intestinal epithelium would disrupt intestinal epithelial morphogenesis and function. To test this hypothesis, we used a conditional knockout approach to eliminate E-cadherin specifically in the intestinal epithelium during embryonic development. We found that E-cadherin conditional knockout mice failed to survive, dying within the first 24 hours of birth. Examination of intestinal architecture at E18.5 demonstrated severe disruption to intestinal morphogenesis in animals lacking E-cadherin in the epithelium of the small intestine. We observed changes in epithelial cell shape as well as in the morphology of villi. Although junctional complexes were evident, junctions were abnormal, and barrier function was compromised in E-cadherin mutant intestine. We also identified changes in the epithelial cell populations present in E-cadherin conditional knockout animals. The number of proliferating cells was increased, whereas the number of enterocytes was decreased. Although Wnt/β-catenin target mRNAs were more abundant in mutants compared with controls, the amount of nuclear activated β-catenin protein was dramatically lower in mutants compared with controls. In summary, our data demonstrate that E-cadherin is essential for intestinal epithelial morphogenesis and homeostasis during embryonic development.
► E-cadherin loss in the developing intestinal epithelium caused neonatal lethality. ► Intestinal epithelial architecture was severely disrupted in E-cadherin mutants. ► Barrier function was compromised in E-cadherin mutants. ► Mutant intestine contained more proliferating cells but fewer enterocytes. ► β-catenin target gene expression was increased, but β-catenin was less abundant in mutants.
Introduction
We tested sex‐dependent associations of variation in the SNAP‐25 gene, which encodes a presynaptic protein involved in hippocampal plasticity and memory, on cognitive and Alzheimer's ...disease (AD) neuroimaging outcomes in clinically normal adults.
Methods
Participants were genotyped for SNAP‐25 rs1051312 (T > C; SNAP‐25 expression: C‐allele > T/T). In a discovery cohort (N = 311), we tested the sex by SNAP‐25 variant interaction on cognition, Aβ‐PET positivity, and temporal lobe volumes. Cognitive models were replicated in an independent cohort (N = 82).
Results
In the discovery cohort, C‐allele carriers exhibited better verbal memory and language, lower Aβ‐PET positivity rates, and larger temporal volumes than T/T homozygotes among females, but not males. Larger temporal volumes related to better verbal memory only in C‐carrier females. The female‐specific C‐allele verbal memory advantage was evidenced in the replication cohort.
Conclusions
In females, genetic variation in SNAP‐25 is associated with resistance to amyloid plaque formation and may support verbal memory through fortification of temporal lobe architecture.
Highlights
The SNAP‐25 rs1051312 (T > C) C‐allele results in higher basal SNAP‐25 expression.
C‐allele carriers had better verbal memory in clinically normal women, but not men.
Female C‐carriers had higher temporal lobe volumes, which predicted verbal memory.
Female C‐carriers also exhibited the lowest rates of amyloid‐beta PET positivity.
The SNAP‐25 gene may influence female‐specific resistance to Alzheimer's disease (AD).
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.
We conducted a joint analysis of 5,523,934 imputed SNPs in two ...newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.
We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10
, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10
). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson's disease and amyotrophic lateral sclerosis.
In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.
Objective: We aimed to test the hypothesis that elevated neocortical β-amyloid (Aβ), a hallmark feature of Alzheimer's disease (AD), predicts sex-specific cognitive trajectories in clinically normal ...older adults, with women showing greater risk of decline than men. Method: Florbetapir Aβ positron emission tomography (PET) was acquired in 149 clinically normal older adults (52% female, Mage = 74). Participants underwent cognitive testing at baseline and during annual follow-up visits over a timespan of up to 5.14 years. Mixed-effects regression models evaluated whether relations between baseline neocortical Standardized Uptake Value Ratio (SUVR) and composite scores of episodic memory, executive functioning, and processing speed were moderated by sex (male/female) and apolipoprotein E (APOE) status (ε4 carrier/noncarrier). Results: Higher baseline SUVR was associated with longitudinal decline in episodic memory in women (b = −1.32, p < .001) but not men (b = −0.30, p = .28). Female APOE ε4 carriers with elevated SUVR showed particularly precipitous declines in episodic memory (b = −4.33, p < .001) whereas other cognitive domains were spared. SUVR did not predict changes in executive functioning or processing speed, regardless of sex (ps >.63), though there was a main effect of SUVR on processing speed (b = 2.50, p = .003). Conclusions: Clinically normal women with elevated Aβ are more vulnerable to episodic memory decline than men. Understanding sex-related differences in AD, particularly in preclinical stages, is crucial for guiding precision medicine approaches to early detection and intervention.
Key Points
Question: This study evaluated whether older men and women are differentially susceptible to cognitive decline in very early, presymptomatic stages of the Alzheimer's disease (AD) continuum. Findings: Our results indicated that clinically normal women with elevated β-amyloid (a protein associated with AD that accumulates in the brain) show significantly greater rates of memory decline over time compared with men, especially when they carry the apolipoprotein E (APOE) ε4 allele (a genetic risk factor for AD). Importance: These findings suggest that women are particularly vulnerable to memory changes in early stages of AD and may help to improve early diagnosis and intervention efforts. Next Steps: Future work should investigate biological (e.g., hormonal, immunological, and cardiovascular), sociocultural (e.g., educational and occupational disparities), and other factors that may help to explain why women are disproportionately at risk for early AD-related cognitive changes.
IMPORTANCE: Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive ...supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. OBJECTIVE: To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND PARTICIPANTS: We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES: Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. RESULTS: Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P = .0049, European P = .041, African American P = .043, and Asian P = .027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P = 5.53 × 10−5) and PAXIP1 (P = 2.26 × 10−4), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE: Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.
Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological, and clinical outcomes in frontotemporal lobar degeneration (FTLD) and ...amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical, neuroglial tauopathy in cases harboring a TMEM106B rs1990622 A/A genotype. To test whether TMEM106B genotype affects the risk of developing atypical tauopathy under a recessive genotype model (presence versus absence of two major alleles: A/A vs. A/G and G/G). We characterized the atypical tauopathy neuropathologically and determined its frequency by TMEM106B rs1990622 genotypes in 90 postmortem cases with a primary diagnosis of FTLD/ALS‐TDP mean age at death 65.5 years (±8.1), 40% female. We investigated the effect of this new atypical tauopathy on demographics and clinical and neuropsychological metrics. We also genotyped TMEM106B in an independent series with phenotypically similar cases. Sixteen cases (16/90, 17.7 %) showed the temporal‐predominant neuro‐astroglial tauopathy, and 93.7% of them carried an A/A genotype (vs. ~35% in a population cohort). The odds ratio of FTLD/ALS‐TDP individuals with the A/A genotype showing neuro‐astroglial tauopathy was 13.9. Individuals with this tauopathy were older at onset (p = 0.01). The validation cohort had a similarly high proportion of rs1990622 A/A genotype. TDP‐43 and tau changes co‐occur in a subset of neurons. Our data add to the growing body of evidence that TMEM106B polymorphisms may modulate neurodegeneration. A distinctive medial temporal predominant, 4‐repeat, neuro‐astroglial tauopathy strongly correlates to TMEM106B A/A genotype in FTLD/ALS‐TDP cases.
noFTLD‐TDP cases with a TMEM106b A/A genotype have a much‐increased odds to show a distinct temporal‐predominant neuro‐astroglial tauopahty.
In the present study, functional skeletal myotubes were efficiently generated from human induced pluripotent stem cells using a small molecule‐based approach. Myotubes derived from patients carrying ...the C9orf72 repeat expansion show no change in differentiation efficiency and normal TDP‐43 localization after as many as 120 days in vitro when compared to unaffected controls. The protocol described in this study for the generation of skeletal myotubes from human induced pluripotent stem cells may serve as a valuable tool in drug discovery and modeling of musculoskeletal and neuromuscular diseases.
Acknowledgements
Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to be used for the study of underlying molecular biology of disease, therapeutic drug screening, and transplant‐based regenerative medicine. However, methods for the directed differentiation of skeletal muscle for these purposes remain scarce and incomplete. Here, we present a novel, small molecule‐based protocol for the generation of multinucleated skeletal myotubes using eight independent iPSC lines. Through combinatorial inhibition of phosphoinositide 3‐kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) with addition of bone morphogenic protein 4 (BMP4) and fibroblast growth factor 2 (FGF2), we report up to 64% conversion of iPSCs into the myogenic program by day 36 as indicated by MYOG+ cell populations. These cells began to exhibit spontaneous contractions as early as 34 days in vitro in the presence of a serum‐free medium formulation. We used this protocol to obtain iPSC‐derived muscle cells from frontotemporal dementia (FTD) patients harboring C9orf72 hexanucleotide repeat expansions (rGGGGCC), sporadic FTD, and unaffected controls. iPSCs derived from rGGGGCC carriers contained RNA foci but did not vary in differentiation efficiency when compared to unaffected controls nor display mislocalized TDP‐43 after as many as 120 days in vitro. This study presents a rapid, efficient, and transgene‐free method for generating multinucleated skeletal myotubes from iPSCs and a resource for further modeling the role of skeletal muscle in amyotrophic lateral sclerosis and other motor neuron diseases.
Protocols to produce skeletal myotubes for disease modeling or therapy are scarce and incomplete. The present study efficiently generates functional skeletal myotubes from human induced pluripotent stem cells using a small molecule‐based approach. Using this strategy, terminal myogenic induction of up to 64% in 36 days and spontaneously contractile myotubes within 34 days were achieved. Myotubes derived from patients carrying the C9orf72 repeat expansion show no change in differentiation efficiency and normal TDP‐43 localization after as many as 120 days in vitro when compared to unaffected controls. This study provides an efficient, novel protocol for the generation of skeletal myotubes from human induced pluripotent stem cells that may serve as a valuable tool in drug discovery and modeling of musculoskeletal and neuromuscular diseases.
OBJECTIVE:To identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease.
METHODS:Four hundred sixty-three non-Hispanic white individuals ...exceeding quality control criteria were included from the Alzheimerʼs Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center.
RESULTS:The minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 × 10, empiric family-wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 × 10; joint analysis p = 1.2 × 10). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 × 10), IL2RA (rs7072793, rs7073236) (p = 7.89 × 10), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 × 10) were identified as suggestive loci associated with plasma tau levels.
CONCLUSIONS:MAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.
PDF
