萩原 英雄

AIMS: Alzheimer's disease (AD) is a leading cause of dementia, with increasing prevalence. Mutations in genes like MAPT, PSEN1, and PSEN2 are risk factors, leading to the development of several AD model mice. Recent hypotheses suggest AD brain pathology involves abnormal neurodevelopment, decreased pH, and neural hyperexcitation. However, it remains unclear to what extent these pathologies are reflected in the gene expression changes of AD models. This study aims to compare gene expression patterns in the brains of multiple AD model mice with those related to these three factors, evaluating the extent of overlap. METHODS: We conducted a comprehensive search of public databases, collecting 20 gene expression datasets from the hippocampus of AD model mice. These datasets were compared with gene sets related to hippocampal maturation, brain pH, and neural hyperexcitation to statistically assess overlap. Pathway enrichment analysis explored the biological relevance of these gene expression changes. RESULTS: The extent of overlap with maturity-, pH-, and hyperexcitation-associated genes varied across AD models, showing significant correlations between lower maturity, lower pH, and increased neural hyperexcitation. In MAPT mutant and APP+PSEN1 homozygous transgenic mice, these signatures became more pronounced with age. Pathway meta-analysis revealed that genes associated with maturity, pH, and hyperexcitation in AD models are involved in synaptic and channel functions, as well as inflammatory responses, consistent with previous studies. CONCLUSION: These findings suggest that pathophysiological changes related to maturity, pH, and neural hyperexcitation play varying roles across individual AD model mice. Our recent study found a negative correlation between disease progression and actual pH levels in human AD patients. Considering the results presented in this study, maturity and neural hyperexcitation, which are correlated with pH, may also be linked to disease progression. Thus, gene expression changes in these factors could be useful markers for assessing the pathology in AD models.

Abstract Introduction Major depressive disorder (MDD) is a prevalent and debilitating mental disorder that shares symptoms, genetics, and molecular changes in the brain with other psychiatric disorders, such as schizophrenia and bipolar disorder. Decreased brain pH, associated with increased lactate levels due to altered energy metabolism and neuronal hyperexcitation, has been consistently observed in schizophrenia and bipolar disorder. We recently demonstrated similar brain alterations in various animal models of neuropsychiatric disorders, including MDD. However, our understanding of brain pH alterations in human patients with MDD remains limited. Methods We conducted meta-analyses to assess postmortem brain pH in patients with MDD compared to control subjects, examining its relationships with recurrence of depressive episodes and illness duration, utilizing publicly available demographic data. Studies reporting individual raw pH data were identified through searches in the Stanley Medical Research Institute database, NCBI GEO database, PubMed, and Google Scholar. The data were analyzed using the random effects model, ANOVA, and ANCOVA. Results The random effects model, using 39 curated datasets (790 patients and 957 controls), indicated a significant decrease in brain pH in patients with MDD (Hedges’ g = −0.23, p = 0.0056). A two-way ANCOVA revealed that the effect of diagnosis on pH remained significant when considering covariates, including postmortem interval, age at death, and sex. Patients with recurrent episodes, but not a single episode, showed significantly lower pH than controls in both females and males (256 patients and 279 controls from seven datasets). Furthermore, a significant negative correlation was observed between brain pH and illness duration (115 patients from five datasets). Female preponderance of decreased pH was also found, possibly due to a longer illness duration and a higher tendency of recurrent episodes in females. Conclusion This study suggests a decrease in brain pH in patients with MDD, potentially associated with recurrent episodes and longer illness duration. As suggested from previous animal model studies, altered brain energy metabolism, leading to decreased pH, may serve as a potential transdiagnostic endophenotype for MDD and other neuropsychiatric disorders.

Abstract Background Altered brain energy metabolism is implicated in Alzheimer’s disease (AD). Limited and conflicting studies on brain pH changes, indicative of metabolic alterations associated with neural activity, warrant a comprehensive investigation into their relevance in this neurodegenerative condition. Furthermore, the relationship between these pH changes and established AD neuropathological evaluations, such as Braak staging, remains unexplored. Methods We conducted quantitative meta-analyses on postmortem brain and cerebrospinal fluid pH in patients with AD and non-AD controls, using publicly available demographic data. We collected raw pH data from studies in the NCBI GEO, PubMed, and Google Scholar databases. Results Our analysis of 20 datasets (723 patient samples and 524 control samples) using a random-effects model showed a significant decrease in brain and cerebrospinal fluid pH in patients compared to controls (Hedges’ g = -0.57, p < 0.0001). This decrease remained significant after considering postmortem interval, age at death, and sex. Notably, pH levels were negatively correlated with Braak stage, indicated by the random-effects model of correlation coefficients from 15 datasets (292 patient samples and 159 control samples) (adjusted r = -0.26, p < 0.0001). Furthermore, brain pH enhanced the discriminative power of the APOEε4 allele, the most prevalent risk gene for AD, in distinguishing patients from controls in a meta-analysis of four combined datasets (95 patient samples and 87 control samples). Conclusions The significant decrease in brain pH in AD underlines its potential role in disease progression and diagnosis. This decrease, potentially reflecting neural hyperexcitation, could enhance our understanding of neurodegenerative pathology and aid in developing diagnostic strategies.

Abstract Background Altered brain energy metabolism is implicated in Alzheimer’s disease (AD). Limited and conflicting studies on brain pH changes, indicative of metabolic alterations associated with neural activity, warrant a comprehensive investigation into their relevance in this neurodegenerative condition. Furthermore, the relationship between these pH changes and established AD neuropathological evaluations, such as Braak staging, remains unexplored. Methods We conducted quantitative meta-analyses on postmortem brain and cerebrospinal fluid pH in patients with AD and non-AD controls, using publicly available demographic data. We collected raw pH data from studies in the NCBI GEO, PubMed, and Google Scholar databases. Results Our analysis of 17 datasets (457 patients and 315 controls) using a random-effects model showed a significant decrease in brain and cerebrospinal fluid pH in patients compared to controls (Hedges’g= –0.54,p< 0.0001). This decrease remained significant after considering postmortem interval, age at death, and sex. Notably, pH levels were negatively correlated with Braak stage, indicated by the random-effects model of correlation coefficients from 15 datasets (292 patients and 159 controls) (adjustedr= –0.26,p< 0.0001). Furthermore, brain pH enhanced the discriminative power of theAPOEε4 allele, the most prevalent risk gene for AD, in distinguishing patients from controls in a meta-analysis of four combined datasets (95 patients and 87 controls). Conclusions The significant decrease in brain pH in AD underlines its potential role in disease progression and diagnosis. This decrease, potentially reflecting neural hyperexcitation, could enhance our understanding of neurodegenerative pathology and aid in developing diagnostic strategies.

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.