The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 ...poly-T with the risk and age of onset of late-onset Alzheimer's disease (LOAD). Following the original discovery, additional studies found associations between the TOMM40 poly-T and LOAD-related phenotypes independent of APOE genotypes, while others did not replicate these associations. Furthermore, the identity of the TOMM40 poly-T risk allele has been controversial between different LOAD-related phenotypes. Here, we propose a framework to address the conflicting findings with respect to the TOMM40 poly-T allele associations with LOAD phenotypes and their functional effects. The framework is used to interpret previous studies as means to gain insights regarding the nature of the risk allele, very long versus short. We suggest that the identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated, the ages of the study subjects at the time of assessment, and the context of the APOE genotypes. In concluding remarks, we outline future studies that will inform the mechanistic interpretation of the genetic data.
•TOMM40 poly-T has autonomous associations with late-onset Alzheimer's disease–related phenotypes.•The direction of the TOMM40 poly-T effects are influenced by interactions with APOE.•The identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated and the ages of the study subjects.
Pioglitazone (PIO) is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPARγ agonists may be ...useful for treating or delaying the onset of Alzheimer's disease (AD), possibly via actions on mitochondria, and that dose strengths lower than those clinically used for T2DM may be efficacious. Our major objective was to determine if low doses of pioglitazone, administered orally, impacted brain activity. We measured blood-oxygenation-level dependent (BOLD) low-frequency fluctuations in conscious rats to map changes in brain resting-state functional connectivity due to daily, oral dosing with low-dose PIO. The connectivity in two neural circuits exhibited significant changes compared with vehicle after two days of treatment with PIO at 0.08 mg/kg/day. After 7 days of treatment with a range of PIO dose-strengths, connections between 17 pairs of brain regions were significantly affected. Functional connectivity with the CA1 region of the hippocampus, a region that is involved in memory and is affected early in the progression of AD, was specifically investigated in a seed-based analysis. This approach revealed that the spatial pattern of CA1 connectivity was consistent among all dose groups at baseline, prior to treatment with PIO, and in the control group imaged on day 7. Compared to baseline and controls, increased connectivity to CA1 was observed regionally in the hypothalamus and ventral thalamus in all PIO-treated groups, but was least pronounced in the group treated with the highest dose of PIO. These data support our hypothesis that PIO modulates neuronal and/or cerebrovascular function at dose strengths significantly lower than those used to treat T2DM and therefore may be a useful therapy for neurodegenerative diseases including AD.
The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer's disease (LOAD) and other age-related conditions.
Here we ...developed the first humanized mouse model that contains the entire TOMM40 and APOE genes with all intronic and intergenic sequences including the upstream and downstream regions. Thus, the mouse model carries the human TOMM40 and APOE genes and their intact regulatory sequences.
We generated the APOE-TOMM40 humanized mouse model in which the entire mouse region was replaced with the human (h)APOE-TOMM40 loci including their upstream and downstream flanking regulatory sequences using recombineering technologies. We then measured the expression of the human TOMM40 and APOE genes in the mice brain, liver, and spleen tissues using TaqMan based mRNA expression assays.
We investigated the effects of the '523' polyT genotype (S/S or VL/VL), sex, and age on the human TOMM40- and APOE-mRNAs expression levels using our new humanized mouse model. The analysis revealed tissue specific and shared effects of the '523' polyT genotype, sex, and age on the regulation of the human TOMM40 and APOE genes. Noteworthy, the regulatory effect of the '523' polyT genotype was observed for all studied organs.
The model offers new opportunities for basic science, translational, and preclinical drug discovery studies focused on the APOE genomic region in relation to LOAD and other conditions in adulthood.
Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer's disease, and longevity. Peroxisome Proliferator ...Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear transcription factor that plays a role in human complex traits that are also genetically associated with the chromosome 19q13.32 region. Here, we study the effects of PPARγ on the regional expression regulation of the genes clustered within chromosome 19q13.32, specifically TOMM40, APOE, and APOC1, applying two complementary approaches. Using the short hairpin RNA (shRNA) method in the HepG2 cell-line we knocked down PPARγ expression and measured the effect on mRNA expression. We discovered PPARγ knock down increased the levels of TOMM40-, APOE-, and APOC1-mRNAs, with the highest increase in expression observed for APOE-mRNA. To complement the PPARγ knockdown findings we also examined the effects of low doses of PPARγ agonists (nM range) on mRNA expression of these genes. Low (nM) concentrations of pioglitazone (Pio) decreased transcription of TOMM40, APOE, and APOC1 genes, with the lowest mRNA levels for each gene observed at 1.5nM. Similar to the effect of PPARγ knockdown, the strongest response to pioglitazone was also observed for APOE-mRNA, and rosiglitazone (Rosi), another PPARγ agonist, produced results that were consistent with these. In conclusion, our results further established a role for PPARγ in regional transcriptional regulation of chr19q13.32, underpinning the association between PPARγ, the chr19q13.32 genes cluster, and human complex traits and disease.
•Chromosome 19q13.32 is a gene rich region that contains the TOMM40-APOE-APOC1 genes and implicated in multiple phenotypes.•This region exhibits a complex regulation and is enriched in potential PPARγ binding sites.•γ knockdown resulted in increased levels of TOMM40, APOE and APOC1 –mRNAs, showing the strongest impact on APOE-mRNA.•Low doses of PPARγ agonists decreased the levels of the TOMM40, APOE and APOC1-mRNAs, with the greatest effect on APOE-mRNA.
•Sex modifies the relationship between TOMM40 ‘650 and network strength•interactions between ‘650, sex, and age were in APOE4 carriers’ neural networks•Older ‘650 G and APOE4 carriers showed less ...neural network connectivity
The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G versus A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while ‘650 G versus A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G-carriage led to less network strength with increasing age, while in non-G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.
Alzheimer’s disease is a quintessential ‘unmet medical need’, accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the ...cost of caring for Alzheimer’s sufferers was $244B, not including the emotional and physical toll on caregivers. In spite of this dismal reality, no treatments are available that reduce the risk of developing AD or that offer prolonged mitiagation of its most devestating symptoms. This review summarizes key aspects of the biology and genetics of Alzheimer’s disease, and we describe how pioglitazone improves many of the patholophysiological determinants of AD. We also summarize the results of pre-clinical experiments, longitudinal observational studies, and clinical trials. The results of animal testing suggest that pioglitazone can be corrective as well as protective, and that its efficacy is enhanced in a time- and dose-dependent manner, but the dose-effect relations are not monotonic or sigmoid. Longitudinal cohort studies suggests that it delays the onset of dementia in individuals with pre-existing type 2 diabetes mellitus, which small scale, unblinded pilot studies seem to confirm. However, the results of placebo-controlled, blinded clinical trials have not borne this out, and we discuss possible explanations for these discrepancies.
Peroxisome proliferator-activated receptor γ (PPARγ) agonists,
including the glitazone class of drugs, are insulin sensitizers that
reduce glucose and lipid levels in patients with type 2 diabetes
...mellitus. To more fully understand the molecular mechanisms underlying
their therapeutic actions, we have characterized the effects of the
potent, tyrosine-based PPARγ ligand GW1929 on serum glucose and lipid
parameters and gene expression in Zucker diabetic fatty rats. In
time-course studies, GW1929 treatment decreased circulating FFA levels
before reducing glucose and triglyceride levels. We used a
comprehensive and unbiased messenger RNA profiling technique to
identify genes regulated either directly or indirectly by PPARγ in
epididymal white adipose tissue, interscapular brown adipose
tissue, liver, and soleus skeletal muscle. PPARγ activation
stimulated the expression of a large number of genes involved in
lipogenesis and fatty acid metabolism in both white adipose tissue and
brown adipose tissue. In muscle, PPARγ agonist treatment decreased
the expression of pyruvate dehydrogenase kinase 4, which represses
oxidative glucose metabolism, and also decreased the expression of
genes involved in fatty acid transport and oxidation. These changes
suggest a molecular basis for PPARγ-mediated increases in glucose
utilization in muscle. In liver, PPARγ activation coordinately
decreased the expression of genes involved in gluconeogenesis. We
conclude from these studies that the antidiabetic actions of PPARγ
agonists are probably the consequence of 1) their effects on FFA
levels, and 2), their coordinate effects on gene expression in multiple
insulin-sensitive tissues.
It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with ...longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that “one-size-fits-all” for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.
Inhibition of acetyl‐CoA carboxylase (ACC) may prevent lipid‐induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly ...conserved amongst animals, only the yeast enzyme structure is available for rational drug design. The use of biophysical assays has permitted the identification of a specific C‐terminal truncation of the 826‐residue human ACC2 carboxyl transferase (CT) domain that is both functionally competent to bind inhibitors and crystallizes in their presence. This C‐terminal truncation led to the determination of the human ACC2 CT domain–CP‐640186 complex crystal structure, which revealed distinctions from the yeast‐enzyme complex. The human ACC2 CT‐domain C‐terminus is comprised of three intertwined α‐helices that extend outwards from the enzyme on the opposite side to the ligand‐binding site. Differences in the observed inhibitor conformation between the yeast and human structures are caused by differing residues in the binding pocket.
Type 2 diabetes is associated with insulin resistance in peripheral tissues, such as muscle and fat, impaired glucose-stimulated insulin secretion from pancreatic β-cells and elevated hepatic ...gluconeogenesis. Current pharmacotherapy does not adequately address the metabolic defects underlying this disease. Thus, novel targets are being explored that enhance insulin action at target tissues, stimulate carbohydrate and fat catabolism, decrease endogenous glucose production and increase pancreatic β-cell neogenesis and glucose-dependent insulin secretion. This article reviews recent developments in research on several of these targets, namely acetyl-CoA carboxylase 2 (ACC2), I kappa kinase (IKK) beta, dipeptidyl peptidase IV (DPP-IV) and glucagon-like peptide-1 receptor (GLP-1R).
PDF
