Atherosclerosis is a leading cause of cardiovascular disease and mortality worldwide. Alterations in the gut microbiota composition, known as gut dysbiosis, have been shown to contribute to atherosclerotic cardiovascular disease (ACVD) development through several pathways. Disruptions in gut homeostasis are associated with activation of immune processes and systemic inflammation. The gut microbiota produces several metabolic products, such as trimethylamine (TMA), which is used to produce the proatherogenic metabolite trimethylamine-N-oxide (TMAO). Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, and certain bile acids (BAs) produced by the gut microbiota lead to inflammation resolution and decrease atherogenesis. Chronic low-grade inflammation is associated with common risk factors for atherosclerosis, including metabolic syndrome, type 2 diabetes mellitus (T2DM), and obesity. Novel strategies for reducing ACVD include the use of nutraceuticals such as resveratrol, modification of glucagon-like peptide 1 (GLP-1) levels, supplementation with probiotics, and administration of prebiotic SCFAs and BAs. Investigation into the relationship between the gut microbiota, and its metabolites, and the host immune system could reveal promising insights into ACVD development, prognostic factors, and treatments.

G protein–coupled receptors (GPCRs) have been shown to play integral roles in Alzheimer’s disease pathogenesis. However, it is unclear how diverse GPCRs similarly affect Aβ and tau pathogenesis. GPCRs share a common mechanism of action via the β-arrestin scaffolding signaling complexes, which not only serve to desensitize GPCRs by internalization, but also mediate multiple downstream signaling events. As signaling via the GPCRs, β2-adrenergic receptor (β2AR), and metabotropic glutamate receptor 2 (mGluR2) promotes hyperphosphorylation of tau, we hypothesized that β-arrestin1 represents a point of convergence for such pathogenic activities. Here, we report that β-arrestins are not only essential for β2AR and mGluR2-mediated increase in pathogenic tau but also show that β-arrestin1 levels are increased in brains of Frontotemporal lobar degeneration (FTLD-tau) patients. Increased β-arrestin1 in turn drives the accumulation of pathogenic tau, whereas reduced ARRB1 alleviates tauopathy and rescues impaired synaptic plasticity and cognitive impairments in PS19 mice. Biochemical and cellular studies show that β-arrestin1 drives tauopathy by destabilizing microtubules and impeding p62/SQSTM1 autophagy flux by interfering with p62 body formation, which promotes pathogenic tau accumulation.

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation, and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), with the CHCHD2-T61I mutation being the most widely studied. However, at present, only CHCHD2 knockout or CHCHD2/CHCHD10 double knockout mouse models have been investigated. They do not recapitulate the pathology seen in patients with CHCHD2 mutations. We generated the first transgenic mouse model expressing the human PD-linked CHCHD2-T61I mutation driven by the mPrP promoter. We show that CHCHD2-T61I Tg mice exhibit perinuclear mitochondrial aggregates, neuroinflammation, and have impaired long-term synaptic plasticity associated with synaptic dysfunction. Dopaminergic neurodegeneration, a hallmark of PD, is also observed along with α-synuclein pathology. Significant motor dysfunction is seen with no changes in learning and memory at one year of age. A minor proportion of the CHCHD2-T61I Tg mice (~10%) show a severe motor phenotype consistent with human Pisa Syndrome, an atypical PD phenotype. Unbiased proteomics analysis reveals surprising increases in many insoluble proteins predominantly originating from mitochondria and perturbing multiple canonical biological pathways as assessed by Ingenuity Pathway Analysis, including neurodegenerative disease-associated proteins such as tau, cofilin, SOD1, and DJ-1. Overall, CHCHD2-T61I Tg mice exhibit pathological and motor changes associated with LBDs, indicating that this model successfully captures phenotypes seen in human LBD patients with CHCHD2 mutations, and demonstrates changes in neurodegenerative disease-associated proteins, which delineates relevant pathological pathways for further investigation.