Alzheimer's disease is a progressive neurodegenerative disorder and the most common form of dementia. Like many neurological disorders, Alzheimer's disease has a sex‐biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular pathology in females and males using the 5XFamilial Alzheimer's disease mutations (5XFAD) genetic mouse model of Alzheimer's disease. We profiled the transcriptome and proteome of the mouse hippocampus during early stages of disease development (1, 2, and 4 months of age). Our analysis reveals 42 genes that are differentially expressed between disease and wild‐type animals at 2 months of age, prior to observable plaque deposition. In 4‐month‐old animals, we detect 1,316 differentially expressed transcripts between transgenic and control 5XFAD mice, many of which are associated with immune function. Additionally, we find that some of these transcriptional perturbations are correlated with altered protein levels in 4‐month‐old transgenic animals. Importantly, our data indicate that female 5XFAD mouse exhibit more profound pathology than their male counterparts as measured by differences in gene expression. We also find that the 5XFAD transgenes are more highly expressed in female 5XFAD mice than their male counterparts, which could partially account for the sex‐biased molecular pathology observed in this dataset.

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Background:The R21C mutation in cardiac troponin I (cTnI) prevents PKA-mediated phosphorylation of serines 23 and 24 of cTnI in vivo. Results: Myofilament function is uncoupled from the intracellular [Ca 2ϩ ] and delays muscle relaxation. Conclusion: Long term ablation of cTnI phosphorylation leads to hypertrophy, diastolic dysfunction, and dysautonomia in mice. Significance: Restoration of phosphorylated cTnI may prevent hypertrophic cardiomyopathy and diastolic dysfunction.The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca 2؉ decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca 2؉ -transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca 2؉ transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca 2؉ content. This abnormal Ca 2؉ handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na ؉ -Ca 2؉ exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy.Inherited as an autosomal dominant disease, familial hypertrophic cardiomyopathy (HCM) 2 is the most common genetic disorder of the heart (1). This clinical syndrome is characterized by an increase in left ventricular mass, diastolic dysfunction, and dysautonomia and carries a high incidence of sudden cardiac death (2). In many HCM cases, cardiac contractile dysfunction is attributed to inherited sarcomeric gene mutations, which can clinically present with variable penetrance, even within the same family pedigree (3,4). Within the context of the sarcomere, it is well established that mutations in cardiac troponin (cTn) alter t...

Background Mutations in thin-filament proteins have been linked to hypertrophic cardiomyopathy (HCM), but it has never been demonstrated that variants identified in the TNNC1 (gene encoding troponin C) can evoke cardiac remodeling in-vivo. The goal of this study was to determine whether TNNC1 can be categorized as an HCM susceptibility gene, such that a mouse model can recapitulate the clinical presentation of the proband. Methods and Results The TNNC1-A8V proband diagnosed with severe obstructive HCM at 34-years of age exhibited mild-to-moderate thickening in left and right ventricular walls, decreased left-ventricular dimensions, left-atrial enlargement and hyperdynamic left-ventricular systolic function. Genetically-engineered knock-in mice containing the A8V mutation (heterozygote=KI-TnC-A8V+/−; homozygote=KI-TnC-A8V+/+) were characterized by echocardiography and pressure-volume studies. Three-month-old, KI-TnC-A8V+/+ mice displayed decreased ventricular dimensions, mild diastolic dysfunction, and enhanced systolic function, while KI-TnC-A8V+/− mice displayed cardiac restriction at 14-months of age. KI hearts exhibited atrial enlargement, papillary-muscle hypertrophy and fibrosis. Liquid chromatography-mass spectroscopy was used to determine incorporation of mutant cTnC (~21%) into the KI-TnC-A8V+/− cardiac myofilament. Reduced diastolic sarcomeric length, increased shortening and prolonged Ca2+ and contractile transients were recorded in intact KI-TnC-A8V+/− and KI-TnC-A8V+/+ cardiomyocytes. Ca2+-sensitivity of contraction in skinned fibers increased with mutant gene dose: KI-TnC-A8V+/+ > KI-TnC-A8V+/− > WT, while KI-TnC-A8V+/+ relaxed more slowly upon flash-photolysis of diazo-2. Conclusions The TNNC1-A8V mutant increases the Ca2+-binding affinity of the thin filament, and elicits changes in Ca2+ homeostasis and cellular remodeling, which leads to diastolic dysfunction. These in-vivo alterations further implicate the role of TNNC1 mutations in the development of cardiomyopathy.