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Alzheimer's disease (AD) is the leading cause of dementia and presents a considerable disease burden. Its pathology involves substantial neuronal loss, primarily attributed to neuronal apoptosis. Although sirtuin 4 (SIRT4) has been implicated in regulating apoptosis in various diseases, the role of SIRT4 in AD pathology remains unclear. The study used APP/PS1 mice as an animal model of AD and amyloid-β (Aβ)1-42-treated HT-22 cells as an AD cell model. SIRT4 expression was determined by quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. A Sirt4 knockdown model was established by intracranial injection of lentivirus-packaged sh-SIRT4 and cellular lentivirus transfection. Immunohistochemistry and flow cytometry were used to examine Aβ deposition in mice and apoptosis, respectively. Protein expression was assessed by Western blot analysis. The UCSC and JASPAR databases were used to predict upstream transcription factors of Sirt4. Subsequently, the binding of transcription factors to Sirt4 was analyzed using a dual-luciferase assay and chromatin immunoprecipitation. SIRT4 expression was upregulated in both APP/PS1 mice and Aβ-treated HT-22 cells compared with their respective control groups. Sirt4 knockdown in animal and cellular models of AD resulted in reduced apoptosis, decreased Aβ deposition, and amelioration of learning and memory impairments in mice. Mechanistically, SIRT4 modulates apoptosis via the mTOR pathway and is negatively regulated by the transcription factor signal transducer and activator of transcription 2 (STAT2). Our study findings suggest that targeting the STAT2-SIRT4-mTOR axis may offer a new treatment approach for AD. NEW & NOTEWORTHY The study reveals that in Alzheimer's disease models, SIRT4 expression increases, contributing to neuronal apoptosis and amyloid-β deposition. Reducing SIRT4 lessens apoptosis and amyloid-β accumulation, improving memory in mice. This process involves the mTOR pathway, regulated by STAT2 transcription factor. These findings suggest targeting the STAT2-SIRT4-mTOR axis as a potential Alzheimer's treatment strategy.

Alzheimer disease (AD) is an irreversible neurodegenerative disease, and astrocytes play a key role in its onset and progression. The aim of this study is to analyze the characteristics of neurotoxic astrocytes and identify novel molecular targets for slowing down the progression of AD. Single-nucleus RNA sequencing (snRNA-seq) data were analyzed from various AD cohorts comprising about 210,654 cells from 53 brain tissue. By integrating snRNA-seq data with bulk RNA-seq data, crucial astrocyte types and genes associated with the prognosis of patients with AD were identified. The expression of neurotoxic astrocyte markers was validated using 5 × FAD and wild-type (WT) mouse models, combined with experiments such as western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence. A group of neurotoxic astrocytes closely related to AD pathology was identified, which were involved in inflammatory responses and pathways related to neuron survival. Combining snRNA and bulk tissue data, ZEP36L, AEBP1, WWTR1, PHYHD1, DST and RASL12 were identified as toxic astrocyte markers closely related to disease severity, significantly elevated in brain tissues of 5 × FAD mice and primary astrocytes treated with Aβ. Among them, WWTR1 was significantly increased in astrocytes of 5 × FAD mice, driving astrocyte inflammatory responses, and has been identified as an important marker of neurotoxic astrocytes. snRNA-seq analysis reveals the biological functions of neurotoxic astrocytes. Six genes related to AD pathology were identified and validated, among which WWTR1 may be a novel marker of neurotoxic astrocytes., (© 2024. The Author(s).)

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive decline, behavioural and psychological symptoms of dementia (BPSD) and impairment of activities of daily living (ADL). Early differentiation of AD from mild cognitive impairment (MCI) is necessary., Methods: A total of 458 patients newly diagnosed with AD and MCI were included. Eleven batteries were used to evaluate ADL, BPSD and cognitive function (ABC). Machine learning approaches including XGboost, classification and regression tree, Bayes, support vector machines and logical regression were used to build and verify the new tool., Results: The Alzheimer's Disease Assessment Scale (ADAS-cog) word recognition task showed the best importance in judging AD and MCI, followed by correct numbers of auditory verbal learning test delay recall and ADAS-cog orientation. We also provided a selected ABC-Scale that covered ADL, BPSD and cognitive function with an estimated completion time of 18 min. The sensitivity was improved in the four models., Conclusion: The quick screen ABC-Scale covers three dimensions of ADL, BPSD and cognitive function with good efficiency in differentiating AD from MCI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To reveal the relations between neuropsychiatric symptoms (NPS), stages of cognitive impairment, sex, and daily function in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD)., Methods: A cross-sectional study was conducted from 2014 to 2021 on 1154 patients. Cognitive function, disease severity, NPS, and daily function were evaluated by Mini-mental State Examination, Clinical Dementia Rating Scale, Neuropsychiatric Inventory, and Activities of Daily Living (ADL) respectively. Multivariate logistic regression and linear regression were used to explore the correlations between NPS, disease stage, sex and ADL., Results: Affective disturbance displayed the highest prevalence from MCI (52.7%) to severe dementia due to AD (98.2%). Multivariate logistic regression revealed that aberrant motor behavior displayed higher prevalence between groups from MCI to severe dementia due to AD (OR = 4.710, P < 0.001; OR = 3.141, P < 0.001; OR = 2.722, P = 0.002, respectively). In patients with dementia due to AD, hallucination and depression were more prevalent in female (OR = 1.730, P = 0.001; OR = 2.376, P < 0.001, respectively) while male presented higher prevalence in apathy (OR = 0.608, P = 0.002). Linear regression analysis showed that delusion and sleep disturbance were significantly associated with basic ADL across all dementia due to AD stages (delusion: mild: β = 0.113, P = 0.015; moderate: β = 0.159, P = 0.019; severe: β = 0.317, P = 0.018; sleep disturbance: mild: β = 0.164, P < 0.001; moderate: β = 0.167, P = 0.013; severe: β = 0.308, P = 0.025) while anxiety was correlated with instrumental ADL from MCI to moderate dementia due to AD (MCI: β = 0.119, P = 0.006; mild: β = 0.149, P < 0.001; moderate: β = 0.130, P = 0.042)., Conclusion: Different subitems of NPS are strongly correlated with sex, stage of cognitive impairment, and ADL., Competing Interests: Declaration of Competing Interest The authors have no competing interests to report., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cognitive decline and neuropsychiatric symptoms (NPS) are main clinical manifestations in Alzheimer disease (AD). It is unclear whether the link between specific NPS and cognitive domains exists in AD or mild cognitive impairment (MCI). Our study aimed to examine the association between specific cognitive domain and NPS in AD and MCI, and to evaluate whether this association showed variety in different stages of cognitive impairment., Methods: A total of 458 patients diagnosed as AD or MCI were included in this study. Neuropsychological batteries were applied in the study. The association between NPS and cognitive function were evaluated by multiple linear regression, and its correlation was evaluated by Spearman correlation coefficient., Results: The prevalence of NPS increased with the severity of cognitive impairment, and there were significant differences between MCI and AD. NPS were predominantly associated with cognitive domains, including memory, language, attention, and executive function. Both regression liner analysis and correlation analysis showed delusion, hallucination, and aberrant motor behaviour (AMB) were linked to language and attention. In addition, regression liner analysis illustrated depression, anxiety, and apathy were related to learning and episodic memory. Generally, the delusion, hallucination, and AMB have the broadest impact on cognition., Conclusion: Specific NPS was predominantly associated with different cognitive domains. Symptoms of agitation, delusion and irritability indicate worse cognitive performance. Therefore, cognitive improvement should be a therapeutic strategy in managing NPS in AD., (© 2021 Japanese Psychogeriatric Society.)

Increasing evidence suggests that changes in the triggering receptor expressed on myeloid cells 2 (TREM2) is closely correlated with the pathological development of Alzheimer's disease (AD). However, the biological function and related role of this change remain poorly understood. Higher TREM2 expression has been reported in the brain of AD patients than in normal controls. Here, levels of TREM2 gene and protein levels were observed to be higher in both cortex and hippocampus of the Aβ 1-42 -induced AD mice than in those of the wild type mice. Together with in vitro experimental data, we found that the anti-inflammatory role of TREM2 was, to some extent, limited and potentially counteracted by the hyperactive toll-like receptor 4 (TLR4) in the AD mice. In this context, Interleukin 4 (IL-4), as an agonist of TREM2, was administered to the AD mice to persistently activate TREM2. Interestingly, TREM2 activation in IL-4-treated AD mice led to an elevation in lysosomes and microtubule-associated protein 1 light chain 3 (LC3) II/I expression, demonstrating that the level of microglia autophagy was increased. Increased autophagy significantly downregulated the expression levels of caspase recruitment domain-containing protein 9 (CARD9) and TLR4, potentially weakening the CARD9-TLR4 pathway and suppressing the TLR4-mediated pro-inflammatory effect in IL-4-treated AD mice. Furthermore, data acquired from Morris water maze testing indicated that IL-4 administration could ameliorate cognitive impairment in the AD mice. In conclusion, the findings from in vitro and in vivo experiments suggest that TREM2 might represent a potential drug target to treat neuroinflammation in AD., (© 2020 Wiley Periodicals LLC.)

Background: To investigate the use and adherence of antidementia drugs in elderly patients with dementia from the Memory Clinic of The First Affiliated Hospital of Chongqing Medical University., Methods: Patients were recruited from the Memory Clinic of The First Affiliated Hospital of Chongqing Medical University from December 2010 to December 2018. Medical charts were reviewed, including diagnosis, dosage of antidementia medicines, neuropsychological testing scores, and the further questionnaires were conducted via face-to-face or telephone, included duration of treatment, types of antidementia drugs, and reasons for treatment discontinuation., Results: The data from 422 patients were analysed retrospectively for this study. Three hundred and fifteen were diagnosed with Alzheimer's disease (AD), 67 with mild cognitive impairment (MCI), and 40 with other types of dementia. From the 422 patients, 26.8% were treated with original donepezil (n = 113), 11.6% with generic donepezil (n = 49), 24.6% with memantine (n = 104), 13.3% with huperzine A (n = 56), and 23.7% with a combination of drugs (n = 100). However, 73% of patients discontinued treatment within 1 year of initiation. Patients treated for more than 36 months (37.8%) were more likely to choose combined medication, as compared with patients treated for less than 36 months. Patients with less than 9 years of education (odds ratio (OR): 2.394; 95% CI: 1.508-3.801) were more likely to discontinue treatment than patients with more than 9 years of education. Patients with elevated physical self-maintenance scale (PSMS) scores (OR: 1.195; 95% CI: 1.086-1.316) had a high risk of discontinuation., Conclusions: Overall treatment compliance is relatively poor in memory clinics in Chongqing. Our study demonstrates that higher education may lead to better treatment adherence in dementia care. Combination therapy may increase treatment time. However, poorer PSMS scores are a significant risk factor for treatment discontinuation., (© 2020 Japanese Psychogeriatric Society.)

Clinically, superimposed systemic inflammation generally has significant deleterious effects on the Alzheimer's disease (AD) progression. However, the related molecular mechanisms remain poorly understood. Microglial toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2) are two key regulators of inflammation that may play an essential role in this complex pathophysiological process. In this study, intraperitoneal injection of lipopolysaccharide (LPS) into APP/PS1 transgenic AD model was used to mimic systemic inflammation in the development of AD. Initial results from the cortex showed that compared with wild-type mice, APP/PS1 mice exhibited elevated gene and protein expression levels of both TLR4 and TREM2 with different degree. Interestingly, after LPS treatment, TLR4 expression was persistently up-regulated, while TREM2 expression was significantly down-regulated in APP/PS1 mice, suggesting that the negative regulatory effect of TREM2 on inflammation might be suppressed by LPS-induced hyperactive TLR4. This imbalance of TLR4/TREM2 contributed to microglial over-activation, followed by increased neuronal apoptosis in the cortex of APP/PS1 mice; these changes did not alter the expression level of Aβ 1-42 . Similar alterations were observed in our in vitro experiment with β-amyloid 1-42 (Aβ 1-42 )-treated N9 microglia. Further, Morris water maze (MWM) testing data indicated that LPS administration acutely aggravated cognitive impairment in APP/PS1 mice, suggesting that the addition of systemic inflammation can potentially accelerate the progression of AD. Collectively, we conclude that an imbalance of TLR4/TREM2 may be a potential link between AD and systemic inflammation. TREM2 can serve as a potential therapeutic target for treating systemic inflammation in AD progression.

Inhibition of endocytosis in an Alzheimer's disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ 1-42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ 1-42 -induced cognition changes. ELISA was used to determine AAK1 levels in plasma and Aβ 1-42 levels in brain tissues. Subsequently, the protein or gene levels of AAK1, AP-2, and Rab5 (an early endosome marker) were tested in each group. The cognitive function of Aβ 1-42 -induced mice was significantly declined compared to control group, and the deficits reached a peak on day 14, but partly recovered on day 30. Moreover, the level of Aβ 1-42 detected with ELISA was highest on day 14, but reduced on day 30, paralleling the cognitive changes in the mice in our study. AAK1, AP-2, and Rab5 expression showed the same periodic variation as the changes in cognition. Thus, periodic variation in AAK1 expression is closely correlated to the decline in cognition, and AAK1 might be a suitable indicator for Alzheimer's disease.

Emerging data suggests that mitochondrial dysfunction is prominently involved in Alzheimer disease (AD) progression. Sirtuin-3 (Sirt3) is a member of the sirtuin family of nicotinamide adenine dinucleotide dependent deacetylases that regulates a variety of mitochondrial functions and suppresses mitochondria-related physiology. Here, we determined sirt3 expression in a mouse model of AD. Spatial learning and memory were tested by Morris water maze in APP/PS1 double transgenic mice. The expression of sirt3 was assayed by real-time quantitative PCR and western blotting. Age-and gender-matched wild-type (WT) littermates were used as controls. Cortical sirt3 localization was assessed using immunohistochemistry. The expression of sirt3 mRNA was significantly lower in the cortex of APP/PS1 double transgenic mice than in WT littermates (0.83 ± 0.24 vs. 1.10 ± 0.21, P < 0.05). A comparable reduction was found in sirt3 protein levels using western blotting. The ratio of mean optical density (MOD) of total sirt3/β-actin in the cortex was 0.77 ± 0.11 in APP/PS1 double transgenic mice and 1.34 ± 0.17 in the WT littermates (P < 0.01). Immunohistochemistry showed the same change as western blotting. The ratio of MOD of integral optical density/total area in APP/PS1 and WT littermates was 0.58 ± 0.02 and 0.71 ± 0.05 (P < 0.01). These data show that sirt3 was depleted in APP/PS1 double transgenic mice. The results suggest that mitochondrial sirt3 might participate in the development of AD via mitochondrial dysfunction.

Background/aims: It has been demonstrated that mitochondrial dysfunction is associated with Alzheimer's disease (AD); meanwhile, hypoxia-up-regulated mitochondrial movement regulator (HUMMR) plays an important role in regulating mitochondrial function. The present study aimed to confirm the association between HUMMR and mitochondrial function in AD., Methods: We detected the expression of HUMMR at transcriptional and translational levels in APP/PS1 double transgenic mice using real-time quantitative RT-PCR and Western blotting. Age- and gender-matched wild-type (WT) littermates were used as controls. Mitochondrial morphology was observed in the hippocampus and cortex of APP/PS1 double transgenic mice using transmission electron microscopy., Results: Damage to mitochondrial morphology in the hippocampus and cortex of APP/PS1 double transgenic mice was found, including swelling and cavitations. Our analysis showed no statistical differences in the expression of HUMMR between APP/PS1 double transgenic mice and WT littermates (p > 0.05). These results showed that there was no association between HUMMR and mitochondrial dysfunction in APP/PS1 transgenic mice., Conclusion: These results indicate that HUMMR does not play a key role in mitochondrial dysfunction in the APP/PS1 double transgenic AD mouse., (© 2013 S. Karger AG, Basel.)