Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer's disease.

The etiopathogenesis of late-onset Alzheimer's disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.

Mitochondria-sequestered Aß renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.

Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid ß 42 (Aß42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized Aß (humanized Aß-knockin [hAß-KI] mice) confirmed the association of increased intramitochondrial sequestration of Aß42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk-bearing context. Also, in comparison with global cerebral Aß, intramitochondrial Aß was relatively preserved from activated microglial phagocytosis in aged hAß-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Aß sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial Aß, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.

Elevated Ghrelin Promotes Hippocampal Ghrelin Receptor Defects in Humanized Amyloid-ß Knockin Mice During Aging.

BACKGROUND: Emerging evidence has revealed that dysregulation of the hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), contributes to the pathogenesis of Alzheimer's disease (AD). Specifically, defective GHSR function and resultant hippocampal ghrelin resistance are linked to hippocampal synaptic injury in AD paradigms. Also, AD patients exhibit elevated ghrelin activation. However, the detailed molecular mechanisms of hippocampal GHSR dysfunction and the relevance of ghrelin elevation to hippocampal ghrelin resistance in AD-relevant pathological settings are not fully understood. OBJECTIVE: In the current study, we employed a recently established mouse line of AD risk [humanized amyloid beta knockin (hAß KI mice), also referred to as a mouse model of late-onset AD in previous literature] to further define the role of ghrelin system dysregulation in the development of AD. METHODS: We employed multidisciplinary techniques to determine the change of plasma ghrelin and the functional status of GHSR in hAß KI mice as well as primary neuron cultures. RESULTS: We observed concurrent plasma ghrelin elevation and hippocampal GHSR desensitization with disease progression. Further examination excluded the possibility that ghrelin elevation is a compensatory change in response to GHSR dysfunction. In contrast, further in vitro and in vivo results show that agonist-mediated overstimulation potentiates GHSR desensitization through enhanced GHSR internalization. CONCLUSIONS: These findings suggest that circulating ghrelin elevation is a pathological event underlying hippocampal GHSR dysfunction, culminating in hippocampal ghrelin resistance and resultant synaptic injury in late-onset AD-related settings.

Liver-expressed antimicrobial peptide 2 elevation contributes to age-associated cognitive decline.

Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin (also referred to in literature as "acyl-ghrelin") marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores. Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation. Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.

Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer's disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown. OBJECTIVE: This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice. METHODS: Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-ß (Aß) in hippocampal mitochondrial deficits and serotonin release deficiency. RESULTS: 5xFAD mice exhibited serotonin release decrease and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-ß (Aß) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aß-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings. CONCLUSION: The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions.

Ghrelin system in Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia in seniors. Current efforts to understand the etiopathogenesis of this neurodegenerative disorder have brought forth questions about systemic factors in the development of AD. Ghrelin is a brain-gut peptide that is activated by ghrelin O-acyltransferase (GOAT) and signals via its receptor, growth hormone secretagogue receptor (GHSR). With increasing recognition of the neurotropic effects of ghrelin, the role of ghrelin system deregulation in the development of AD has been accentuated in recent years. In this review, we summarized recent research progress regarding the mechanisms of ghrelin signaling dysregulation and its contribution to AD brain pathology. In addition, we also discussed the therapeutic potential of strategies targeting ghrelin signaling for the treatment of this neurological disease.

Nonobese Male Patients with Alzheimer's Disease Are Vulnerable to Decrease in Plasma Leptin.

BACKGROUND: Metabolic dysfunction links to cognitive deficits in Alzheimer's disease (AD). Leptin is an anti-obesity hormone that modulates energy homeostasis and memory function. Although leptin deregulation is implicated in mouse models of AD-like brain pathology, clinical studies have shown inconsistent results regarding an association of leptin with the development of this neurodegenerative disorder. OBJECTIVE: We investigated the changes of plasma leptin and the correlation of sex-stratified circulating leptin with cognitive performance, AD-related biological markers, and metabolic status in patients with AD and cognitively unimpaired (CU) counterparts. METHODS: We used nonobese AD patients and CU controls in a University of Kansas Medical Center (KUMC) cohort. Plasma leptin levels, circulating AD-related molecules and metabolic profiles were examined and analyzed. RESULTS: In contrast to unchanged circulating leptin in females, male patients exhibited decreased plasma leptin levels compared with male CU counterparts. Moreover, plasma leptin showed no correlation with cognitive performance and AD blood biomarkers in patients with either sex. Of note, females but not males demonstrated an association of plasma leptin with body mass index, high density lipoprotein-cholesterol and its ratio with total cholesterol and triglycerides. CONCLUSION: Our findings suggest that leptin deficiency is associated with nonobese male AD patients, supporting systemic dysmetabolism in the development of this neurodegenerative disorder in certain populations. Although plasma leptin may have limited capacity to reflect disease severity or progression, future mechanistic studies on the regulation of leptin in nonobese patients with AD would deepen our understanding of the sex-related disparity of AD etiopathogenesis.

Social media (Facebook) improper use and the influence of sleeping quality in Taiwan's university students.

This study examines the relationship between Facebook (FB) usage and addiction level, and sleep quality of university students. A Google Forms questionnaire was prepared and disseminated via the authors' FB profile for university students to fill out. A total of 277, including two studying overseas, took part in this research. Among the survey respondents, over 60% (n = 144) were medical students (p = 0.000); over 30% (n = 84) were always logged into FB; the average and daily usage time of most was 5 to 60 min at a time (p = 0.009), and 3 to 5 h a day (p = 0.040), respectively. The respondents' average sleep time was 7.11 h, but over 61% categorized their sleep quality as poor. It was also found that students from financial and management school were 4.23 times more at risk of FB addiction than the medical counterparts and were likely to be already addicted to FB as well as have a sleep disorder. Based on these results, it is suggested that university students, who fall in the high-risk category, be screened early to prevent them from developing social media addiction and sleep disorders. For improving youths' health and sleep quality, future research should attach the importance to early screening for sleep disturbances caused by the internet and social media addiction.

MK0677, a Ghrelin Mimetic, Improves Neurogenesis but Fails to Prevent Hippocampal Lesions in a Mouse Model of Alzheimer's Disease Pathology.

Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer's disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-ß (Aß) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aß toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment.

A Randomized Clinical Efficacy Trial of Red Yeast Rice (Monascus pilosus) Against Hyperlipidemia.

Red yeast rice (RYR) has been used as an alternative treatment for hyperlipidemia. According to the previous studies, other compounds, besides monacolin K in RYR, may also reduce the serum lipid level. This study aims at examining the efficacy of monacolin K-rich and Gamma-Aminobutyric Acid (GABA)-rich RYR (Monascus pilosus) with regards to treating hyperlipidemia in a randomized control, double-blind clinical trial. In the research, we assigned 50 eligible subjects to monacolin K-rich RYR, GABA-rich RYR and placebo groups ( n=16 , 17, 17, respectively). The concentrations of TC, LDL-C, HDL, TG and blood biochemical data were evaluated at different phases: before applying (visit 1), after 1-month (visit 2), 2-month (visit 3), 3-month (visit 4) of providing the intervention and 1-month after ending the test food (visit 5) among three groups. During the 3-month intervention, the serum TC and LDL-C levels decreased significantly in the monacolin K group compared to the baseline and the other two groups. The Serum TG level declined steadily but was not statistically significant. Meanwhile, no marked differences in the serum HDL level were revealed among the three groups. Most safety assessment data had minor variation except two subjects (in monacolin K and GABA group separately) reported elevated liver enzymes. Monacolin K-rich RYR can reduce cholesterol as expected, while the GABA-rich RYR performed non-significant reduction on serum triglyceride. The research results demonstrate that using different concentrations and ratios between monacolin K and GABA could be beneficial for antihyperlipidemia.