The long-term effects of heated tobacco product exposure on the central nervous system in a mouse model of prodromal Alzheimer's disease.

Heated tobacco products (HTPs) have emerged as novel alternatives to conventional cigarettes (CCs), marketed by the tobacco industry as having a reduced potential for harm. Nevertheless, a significant dearth of information remains regarding the long-term effects of HTPs on the central nervous system (CNS). Here, we sought to shed light on the repercussions of prolonged exposure to HTPs on the CNS, employing a mouse model mimicking prodromal Alzheimer's disease (AD). Our study entailed subjecting App knock-in mice to 16 weeks of HTP exposure, administered 5 days per week, with serum cotinine concentration serving as confirmation of HTP exposure within this model. Histological analysis, aimed at assessing amyloid pathology, unveiled a minimal impact attributable to HTPs. However, exploration of differentially expressed genes in the cerebral cortex, using unadjusted p values, indicated an association between HTP exposure and non-inflammatory pathways, specifically linked to neurohypophyseal and neuropeptide hormone activity within the CNS. Of note, similar results have already been observed after exposure to CCs in vivo. Our study not only contributes insights into the potential non-inflammatory effects of HTPs within the context of AD pathogenesis but also underscores the significance of continued research to comprehend the full scope of their impact on the CNS.

Apolipoprotein E genotype-dependent accumulation of amyloid ß in APP-knock-in mouse model of Alzheimer's disease.

Apolipoprotein E4 (APOE4), the strongest risk factor for late-onset Alzheimer's disease (AD), has been revealed to cause greater accumulation of extracellular amyloid ß (Aß) aggregates than does APOE3 in traditional transgenic mouse models of AD. However, concerns that the overexpression paradigm might have affected the phenotype remain. Amyloid precursor protein (APP)-knock-in (KI) mice, incorporating APP mutations associated with AD development, offer an alternative approach for overproducing pathogenic Aß without needing overexpression of APP. Here, we present the results of comprehensive analyses of pathological and biochemical traits in the brains of APP-KI mice harboring APP-associated familial AD mutations (APPNL-G-F/NL-G-F mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aß pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aß in vivo, which may not be addressed appropriately by using other transgenic mouse models.

Alkannin Attenuates Amyloid ß Aggregation and Alzheimer's Disease Pathology.

Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid ß formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid ß aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid ß aggregation. Importantly, we also found that alkannin inhibited amyloid ß aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit ß-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid ß-induced neuronal cell death in PC12 cells, ameliorated amyloid ß aggregation in the AD model of Caenorhabditis elegans (C. elegans), and inhibited chemotaxis observed in AD C. elegans, suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid ß aggregation and neuronal cell death in AD. SIGNIFICANCE STATEMENT: Aggregated amyloid ß formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit ß-sheet structure formation of amyloid ß and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in C. elegans. Overall, alkannin may have novel pharmacological properties for inhibiting amyloid ß aggregation and neuronal cell death in Alzheimer's disease.

Homocysteine causes neuronal leptin resistance and endoplasmic reticulum stress.

Abnormally high serum homocysteine levels have been associated with several disorders, including obesity, cardiovascular diseases or neurological diseases. Leptin is an anti-obesity protein and its action is mainly mediated by the activation of its Ob-R receptor in neuronal cells. The inability of leptin to induce activation of its specific signaling pathways, especially under endoplasmic reticulum stress, leads to the leptin resistance observed in obesity. The present study examined the effect of homocysteine on leptin signaling in SH-SY5Y neuroblastoma cells expressing the leptin receptor Ob-Rb. Phosphorylation of the signal transducer and activator of transcription (STAT3) and leptin-induced STAT3 transcriptional activity were significantly inhibited by homocysteine treatment. These effects may be specific to homocysteine and to the leptin pathway, as other homocysteine-related compounds, namely methionine and cysteine, have weak effect on leptin-induced inhibition of STAT3 phosphorylation, and homocysteine has no impact on IL-6-induced activation of STAT3. The direct effect of homocysteine on leptin-induced Ob-R activation, analyzed by Ob-R BRET biosensor to monitor Ob-R oligomerization and conformational change, suggested that homocysteine treatment does not affect early events of leptin-induced Ob-R activation. Instead, we found that, unlike methionine or cysteine, homocysteine increases the expression of the endoplasmic reticulum (ER) stress response gene, a homocysteine-sensitive ER resident protein. These results suggest that homocysteine may induce neuronal resistance to leptin by suppressing STAT3 phosphorylation downstream of the leptin receptor via ER stress.