Alzheimer's Disease Cognitive Impairment Research Articles

Cardiorespiratory Disturbances in Alzheimer's Disease: A Focus on the Contribution of Sympathetic Premotor Neurons

While therapeutic approaches targeting neurodegenerative mechanisms associated with cognitive impairment in Alzheimer's disease (AD) have been intensively explored, other comorbidities closely linked to AD progression, such as sleep-disordered breathing and autonomic dysfunction, have not been thoroughly investigated. In preliminary studies, we showed an increase in neural activity of catecholaminergic premotor neurons located in the rostral ventrolateral medulla region (RVLM-C1), a main region involved in cardiorespiratory regulation, in experimental AD. Therefore, in the present study, we aimed first to characterize cardiorespiratory function in AD patients and then to determine the role of RVLM-C1 neurons in autonomic and sleep-disordered breathing in APP/PS1 double transgenic mice, an experimental model showing AD-like pathology. Sixteen subjects (8 AD and 8 age-matched controls) were enrolled to assess sleep breathing disorders and to record cardiac autonomic function. Whole-body plethysmography and blood pressure monitoring in freely moving mice were used to study sleep-associated cardiorespiratory disorders. Bilateral stereotaxic injections of anti-dopamine β-hydroxylase-saporin (DβH-SAP) into the RVLM were used to selectively destroy C1 neurons. Compared to age-matched healthy subjects, patients with AD showed larger increases in neural sympathetic discharges during autonomic testing. In addition, heart rate variability analysis in AD patients showed a shift in spectral components towards a more sympathetic influence. Remarkably, we found that autonomic function impairment in the APP/PS1 mice resembles what we found in AD patients. Compared to wild type (WT), APP/PS1 mice displayed sympatho-excitation (ΔHR: -80±5 vs -125±10, WT vs APP/PS1, respectively), a higher incidence of cardiac arrhythmias (events/h 6.0±1.0 vs 12±1.5, WT vs APP/PS1, respectively), and sleep-disordered breathing (AHI: 8.5±2.0 vs 18.0±3.0, WT vs APP/PS1, respectively). Partial ablation of RVLM-C1 neurons (~70%) in APP/PS1 mice resulted in a two-fold and three-fold reduction in cardiac sympathetic drive and arrhythmogenesis, respectively. Furthermore, APP/PS1 mice treated with DβH-SAP showed marked improvements in breathing regularity (IS: 7.9±1.1 vs 16.9±2.2, APP/PS1DβH-SAP vs APP/PS1, respectively) and a restoration of normal sleep effciency (SE: 75.5±4.3 vs 58.1±6.4, APP/PS1DβH-SAP vs APP/PS1, respectively) compared to untreated APP/PS1 mice. Our results show that RVLM-C1 neurons play a main role in the development/maintenance of cardiorespiratory disorders in experimental AD. FONDECYT 11220962, 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Isoform-specific effects of neuronal inhibition of AMPK catalytic subunit on LTD impairments in a mouse model of Alzheimer’s disease

Synaptic dysfunction is highly correlated with cognitive impairments in Alzheimer’s disease (AD), the most common dementia syndrome in the elderly. Long-term potentiation (LTP) and long-term depression (LTD) are two primary forms of synaptic plasticity with opposite direction of synaptic efficiency change. Both LTD and LTD are considered to mediate the cellular process of learning and memory. Substantial studies demonstrate AD-associated deficiency of both LTP and LTD. Meanwhile, the molecular signaling mechanisms underlying impairment of synaptic plasticity, particularly LTD, are poorly understood. By taking advantage of the novel transgenic mouse models recently developed in our lab, here we aimed to investigate the roles of AMP-activated protein kinase (AMPK), a central molecular senor that plays a critical role in maintaining cellular energy homeostasis, in regulation of LTD phenotypes in AD. We found that brain-specific suppression of the AMPKα1 isoform (but not AMPKα2 isoform) was able to alleviate mGluR-LTD deficits in APP/PS1 AD mouse model. Moreover, suppression of either AMPKα isoform failed to alleviate AD-related NMDAR-dependent LTD deficits. Taken together with our recent studies on roles of AMPK signaling in AD pathophysiology, the data indicate isoform-specific roles of AMPK in mediating AD-associated synaptic and cognitive impairments.

Correlation Between Prefrontal Functional Connectivity and the Degree of Cognitive Impairment in Alzheimer's Disease: A Functional Near-Infrared Spectroscopy Study.

The development of Alzheimer's disease (AD) can be divided into subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Early recognition of pre-AD stages may slow the progression of dementia. This study aimed to explore functional connectivity (FC) changes of the brain prefrontal cortex (PFC) in AD continuum using functional near-infrared spectroscopy (fNIRS), and to analyze its correlation with cognitive function. All participants underwent 48-channel fNIRS at resting-state. Based on Brodmann partitioning, the PFC was divided into eight subregions. The NIRSIT Analysis Tool (v3.7.5) was used to analyze mean ΔHbO2 and FC. Spearman correlation analysis was used to examine associations between FC and cognitive function. Compared with HC group, the mean ΔHbO2 and FC were different between multiple subregions in the AD continuum. Both mean ΔHbO2 in the left dorsolateral PFC and average FC decreased sequentially from SCD to MCI to AD groups. Additionally, seven pairs of subregions differed in FC among the three groups: the differences between the MCI and SCD groups were in heterotopic connectivity; the differences between the AD and SCD groups were in left intrahemispheric and homotopic connectivity; whereas the MCI and AD groups differed only in homotopic connectivity. Spearman correlation results showed that FCs were positively correlated with cognitive function. These results suggest that the left dorsolateral PFC may be the key cortical impairment in AD. Furthermore, there are different resting-state prefrontal network patterns in AD continuum, and the degree of cognitive impairment is positively correlated with reduced FC strength.

Aβ peptide enhances GluA1 internalization via lipid rafts in Alzheimer's-related hippocampal LTP dysfunction.

Amyloid β (Aβ) is a central contributor to neuronal damage and cognitive impairment in Alzheimer's disease (AD). Aβ disrupts AMPA receptor-mediated synaptic plasticity, a key factor in early AD progression. Numerous studies propose that Aβ oligomers hinder synaptic plasticity, particularly long-term potentiation (LTP), by disrupting GluA1 (encoded by GRIA1) function, although the precise mechanism remains unclear. In this study, we demonstrate that Aβ mediates the accumulation of GM1 ganglioside in lipid raft domains of cultured cells, and GluA1 exhibits preferential localization in lipid rafts via direct binding to GM1. Aβ enhances the raft localization of GluA1 by increasing GM1 in these areas. Additionally, chemical LTP stimulation induces lipid raft-dependent GluA1 internalization in Aβ-treated neurons, resulting in reduced cell surface and postsynaptic expression of GluA1. Consistent with this, disrupting lipid rafts and GluA1 localization in rafts rescues Aβ-mediated suppression of hippocampal LTP. These findings unveil a novel functional deficit in GluA1 trafficking induced by Aβ, providing new insights into the mechanism underlying AD-associated cognitive dysfunction.

The role of neuropeptides (oxytocin, vasopressin, neuropeptide S) in the development of cognitive impairment in Alzheimer’s disease

Every year, the number of people diagnosed with Alzheimer’s disease is rapidly increasing. Despite numerous studies, it was not possible to select a therapy that would reliably slow down the course of the disease and result in its complete cure. In this case, any consideration of the issue related to the search for drugs to eliminate cognitive and psychoemotional disorders in Alzheimer’s disease is a pressing problem that deserves special attention.We collected articles from the PubMed database published over the past 10 years. The aim of this review was to analyze the latest experimental data and results regarding the relationship between Alzheimer’s disease and the activity of neuropeptides, such as oxytocin, vasopressin, and neuropeptide S, and describing the effects that occur upon their administration. This will allow for a more complete understanding of the problem and update information on this issue. The ability of neuropeptides to restore impaired cognitive functions in an animal model of Alzheimer’s disease is examined in more detail.Detailed information on the relationship and positive effect of the studied neuropeptides on Alzheimer’s disease allows to consider these neuropeptides as potential drugs for the treatment of this disease.

Distinct eye movement patterns to complex scenes in Alzheimer's disease and Lewy body disease.

Alzheimer's disease (AD) and Lewy body disease (LBD), the two most common causes of neurodegenerative dementia with similar clinical manifestations, both show impaired visual attention and altered eye movements. However, prior studies have used structured tasks or restricted stimuli, limiting the insights into how eye movements alter and differ between AD and LBD in daily life. We aimed to comprehensively characterize eye movements of AD and LBD patients on naturalistic complex scenes with broad categories of objects, which would provide a context closer to real-world free viewing, and to identify disease-specific patterns of altered eye movements. We collected spontaneous viewing behaviors to 200 naturalistic complex scenes from patients with AD or LBD at the prodromal or dementia stage, as well as matched control participants. We then investigated eye movement patterns using a computational visual attention model with high-level image features of object properties and semantic information. Compared with matched controls, we identified two disease-specific altered patterns of eye movements: diminished visual exploration, which differentially correlates with cognitive impairment in AD and with motor impairment in LBD; and reduced gaze allocation to objects, attributed to a weaker attention bias toward high-level image features in AD and attributed to a greater image-center bias in LBD. Our findings may help differentiate AD and LBD patients and comprehend their real-world visual behaviors to mitigate the widespread impact of impaired visual attention on daily activities.

PRG ameliorates cognitive impairment in Alzheimer's disease mice by regulating β-amyloid and targeting the ERK pathway

BackgroundPRG is derived from Phellinus ribis and is a homogeneous polysaccharide with well-defined structural information. PRG was found to have significant in vitro neurotrophic and neuroprotective activities. Thus, PRG might be a potential treatment for Alzheimer's disease. However, the related mechanisms of action are still unclear, so deeper in vivo experimental validation and the potential mechanisms need to be investigated. PurposeThe effects of PRG on AD mice were investigated using Senescence-accelerated SAMP8 mice as an AD model to elucidate the crucial molecular mechanisms. MethodsPRG was obtained from Phellinus ribis by water-alcohol precipitation, column chromatography, and ultrafiltration. The Morris water maze and novel object recognition behavioral assays were used to evaluate the effects of PRG in AD mice. Nissl staining, the TUNEL apoptosis assay, and Golgi staining were used to assess brain neuronal cell damage, apoptosis, and neuronal status. Enzyme-linked immunosorbent assays, Western blotting, and immunofluorescence were used to explore the impacts of correlated factors and protein pathways under relevant mechanisms. ResultsThe findings suggest that PRG improved learning ability and spatial memory capacity in SAMP8 mice. PRG hastened the disintegration of β-amyloid, reduced the content and abnormal accumulation of the toxic Aβ1-42 protein, and decreased apoptosis. PRG activated the BDNF/ERK/CREB signaling pathway through a cascade, exerted neurotrophic effects, regulated cell proliferation and differentiation, increased neuronal dendritic branching and spine density, and improved synaptic plasticity. ConclusionPRG promoted β-amyloid degradation to reduce neuronal damage and apoptosis. It exerted neurotrophic effects by activating the BDNF/ERK/CREB pathway, promoting neuronal dendritic branching and dendritic spine growth, regulating cell proliferation and differentiation, and improving synaptic plasticity, which improved AD. Taken together, as a novel natural active polysaccharide with a well-defined structure, PRG affected AD symptoms in senescence-accelerated mice by interacting with multiple targets. The results indicate that PRG is a promising potential anti-AD drug candidate.

Acanthopanax senticosus improves cognitive impairment in Alzheimer's disease by promoting the phosphorylation of the MAPK signaling pathway.

Acanthopanax senticosus (AS) can improve sleep, enhance memory, and reduce fatigue and is considered as an effective drug for Alzheimer's disease (AD). The therapeutic effect and mechanism need to be further investigated. To confirm the AS play efficacy in alleviating memory impairment in mice, 5×FAD transgenic mice were subjected to an open-field experiment and a novelty recognition experiment. Network pharmacology technique was used to analyze the information of key compounds and potential key targets of AS for the treatment of AD, molecular docking technique was applied to predict the binding ability of targets and compounds, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed on the targets to derive the possible metabolic processes and pathway mechanisms of AS in treating AD. Quantitative real-time PCR (qRT-PCR) and western blot technique were carried out to validate the candidate genes and pathways. In the open-field experiment, compared with the wild-type (WT) group, the number of times the mice in the AD group crossed the central zone was significantly reduced (P< 0.01). Compared with the AD group, the number of times the mice in the AS group crossed the central zone was significantly increased (P< 0.001). In the new object recognition experiment, compared with the WT group, the percentage of times the AD group explored new objects was significantly reduced (P< 0.05). Compared with the AD group, the AS group had an increase in the percentage of time spent exploring new things and the number of times it was explored (P< 0.05). At the same time, the donepezil group had a significantly higher percentage of times exploring new things (P< 0.01). By using network pharmacology technology, 395 common targets of AS and AD were retrieved. The Cytoscape software was used to construct the protein-protein interaction (PPI) network of common targets. Using the algorithm, nine key targets were retrieved: APP, NTRK1, ESR1, CFTR, CSNK2A1, EGFR, ESR2, GSK3B, and PAK1. The results of molecular docking indicate that 11 pairs of compounds and their corresponding targets have a significant binding ability, as the molecular binding energies were less than -7.0. In comparison to the AD group, the mRNA expression of the key target genes was significantly decreased in the AS treatment group (P< 0.001). The KEGG analysis showed that the MAPK signaling pathway was significantly enriched, and Western blot confirmed that the TRAF6 protein decreased significantly (P< 0.0001). Meanwhile, the levels of MAP3K7 and P38 phosphorylation increased, and there was also an increase in the expression of HSP27 proteins. Our study indicates that the multi-component and multi-target properties of AS play an important role in the alleviation of anxiety and memory impairment caused by AD, and the mechanism is involved in the phosphorylation and activation of the MAPK signaling pathway. The results of this study could provide a novel perspective for the clinical treatment of AD.

Electroencephalogram-Based Metastability in Mild Cognitive Impairment Alzheimer's Disease.

Background: In this study, we analyze metastability, a feature of brain dynamics in subjects experiencing mild cognitive impairment Alzheimer's disease (MCI-AD) under eyes open (EO) and eyes closed (EC) conditions. Alzheimer's disease (AD) is a critically prolonged brain disorder that interrupts neural synchronization and desynchronization. Thus, studying metastability under EO and EC conditions would help in understanding the cortical dynamics and its impact in early-stage AD. Methods: Metastability is investigated using three methods namely frequency variance analysis, Kuramoto order parameter, and through meta-state activation patterns. Frequency variance estimated from 21 electroencephalogram (EEG) channels was clustered into three regions namely anterior, central, and posterior to study the regional metastability analysis. Global metastability was assessed from Kuramoto order parameter and meta-state activation patterns by collating the 21 EEG channels. Results: Reduction in metastability was observed in central regions of MCI-AD subjects through the study of frequency variance analysis. There was a marked reduction in global metastability in the patient group under the resting EO condition. Reduction in meta-state activation properties such as temporal activation sequence complexity, modularity, and leap size in MCI-AD condition under the EO condition indicates an overall reduction in brain flexibility. Conclusion: Taken together, the study infers an underlying structural change in neuronal dynamics influencing the reduction of metastability under the MCI-AD condition. The study further revealed that this reduction in metastability is more pronounced in the EO condition.

Genetic modifiers of cognitive decline in PSEN1 E280A Alzheimer's disease.

Rate of cognitive decline (RCD) in Alzheimer's disease (AD) determines the degree of impairment for patients and of burden for caretakers. We studied the association of RCD with genetic variants in AD. RCD was evaluated in 62 familial AD (FAD) and 53 sporadic AD (SAD) cases, and analyzed by whole-exome sequencing for association with common exonic functional variants. Findings were validated in post mortem brain tissue. One hundred seventy-two gene variants in FAD, and 227 gene variants in SAD associated with RCD. In FAD, performance decline of the immediate recall of the Rey-Osterrieth figure test associated with 122 genetic variants. Olfactory receptor OR51B6 showed the highest number of associated variants. Its expression was detected in temporal cortex neurons. Impaired olfactory function has been associated with cognitive impairment in AD. Genetic variants in these or other genes could help to identify risk of faster memory decline in FAD and SAD patients.

Dendrobine Ameliorates Alzheimer's Disease-like Pathology and Cognitive Decline in 3 × Tg-AD Mice.

Previous studies have shown that Dendrobium nobile Lindl. alkaloids (DNLAs) have neuroprotective effects in several Alzheimer's disease (AD) models. Dendrobine (DDB) is one of the monomer components with the highest content in DNLAs. However, the effects of DDB on cognitive impairments in AD remain unknown. In this study, we investigated the efficacy of DDB in 3 × Tg-AD mice to determine whether DDB was a key component of the anti-AD effect of DNLAs. Five-month mice were intragastrically administrated with DDB (10 and 20 mg/kg/d) or DNLAs (20 mg/kg/d) for seven consecutive months, and the effects of DDB and DNLAs were evaluated at twelve months. The results revealed that 3 × Tg-AD mice treated with DDB showed enhanced nesting ability. DDB also effectively rescued spatial learning and memory deficits in 3 × Tg-AD mice. Meanwhile, DDB treatment prevented the loss of dendritic spine density, with increased expression levels of synaptophysin, PSD95, and NCAM in the hippocampus. Finally, DDB ameliorated the increase in APP, sAPPβ, CTF-β, and β-amyloid peptides, accompanied by the promotion of GSK phosphorylation at the Ser9 site, thereby reducing hyperphosphorylated tau levels. As the active component of DNLA, DDB can preserve cognitive function, alleviate neuronal and synaptic defects, and improve APP/tau pathology in 3 × Tg-AD mice.

Atypical clinical variants of Alzheimer's disease: are they really atypical?

Alzheimer's disease (AD) is a neuropathological disorder defined by the deposition of the proteins, tau and β-amyloid. Alzheimer's disease is commonly thought of as a disease of the elderly that is associated with episodic memory loss. However, the very first patient described with AD was in her 50's with impairments in multiple cognitive domains. It is now clear that AD can present with multiple different non-amnestic clinical variants which have been labeled as atypical variants of AD. Instead of these variants of AD being considered "atypical," I propose that they provide an excellent disease model of AD and reflect the true clinical heterogeneity of AD. The atypical variants of AD usually have a relatively young age at onset, and they show striking cortical tau deposition on molecular PET imaging which relates strongly with patterns of neurodegeneration and clinical outcomes. In contrast, elderly patients with AD show less tau deposition on PET, and neuroimaging and clinical outcomes are confounded by other age-related pathologies, including TDP-43 and vascular pathology. There is also considerable clinical and anatomical heterogeneity across atypical and young-onset amnestic variants of AD which reflects the fact that AD is a disease that causes impairments in multiple cognitive domains. Future studies should focus on careful characterization of cognitive impairment in AD and consider the full clinical spectrum of AD, including atypical AD, in the design of research studies investigating disease mechanisms in AD and clinical treatment trials, particularly with therapeutics targeting tau.

Oligosaccharides from black ginseng innovatively prepared by low-temperature steam-heating process ameliorate cognitive impairment in Alzheimer's disease mice via the Keap-1/Nrf2 pathway.

Our objective in this study was to evaluate the effectiveness of oligosaccharides extracted from black ginseng (OSBG), innovatively prepared by a low-temperature steam-heating process, in the improvement of learning and memory impairment in mice, as well as the mechanism(s). Eight carbohydrates involving isomaltose and maltotetraose were detected in black gensing; monosaccharide residues including mannose and rhamnose were also discovered. OSBG-treated mice showed significant amelioration in recognition and spatial memory deficits compared to the scopolamine group. OSBG could decrease acetylcholinesterase activity in a tissue-dependent fashion but not in a dose-dependent manner. Furthermore, in contrast, OSBG administration resulted in significant upregulation superoxide dismutase, glutathione, glutathione peroxidase (GPx), and Kelch-like ECH-associated protein 1, downregulation of malondialdehyde and nuclear factor erythroid 2-related factor 2 in the tissues. Finally, at the genus level, we observed that the OSBG interventions increased the relative abundance of probiotics (e.g., Barnesiella, Staphylococcus, Clostridium_XlVb) and decreased pernicious bacteria such as Eisenbergiella and Intestinimonas, compared to the Alzheimer's disease mouse model group. Herein, our results demonstrate that OSBG restores the composition of the scopolamine-induced intestinal microbiota in mice, providing homeostasis of gut microbiota and providing evidence for microbiota-regulated therapeutic potential. Our results showed for the first time a clear role for OSBG in improving scopolamine-induced memory impairment by inhibiting cholinergic dysfunction in a tissue-dependent manner. Additionally, OSBG administration relieved oxidative stress by activating the Keap-1/Nrf2 pathway and modulating the gut microbiota. Collectively, OSBG may be a promising target for neuroprotective antioxidants for improving memory and cognition in Alzheimer's disease patients. © 2024 Society of Chemical Industry.

The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer's disease model mice and its mechanism.

The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData. Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.

Chronic intermittent hypoxia induces cognitive impairment in Alzheimer's disease mouse model via postsynaptic mechanisms.

Obstructive sleep apnea (OSA) is highly comorbid with Alzheimer's disease (AD) and may represent a risk factor for inducing or accelerating cognitive impairment in AD. Chronic intermittent hypoxia (CIH) has beenconsidered to be a predictor of developing cognitive decline and AD. However, the precise underlying mechanisms by which CIH contributes to cognitive impairment remain unknown. In the present study, we examined the effects of CIH on cognition and hippocampal function in APP/PS1 mice, an animal model of AD. Wild-type (WT) and APP/PS1 mice were subjected to one of the following conditions for 2weeks: (1) sham condition (continuous room air) or (2) CIH condition. The oxygen concentration of the CIH condition transitioned from 5 to 21%. Behavioral tests, electrophysiological recording, real-time polymerase chain reaction, and Western blot were used to assess the effect of CIHon cognitive performance and synaptic plasticity. CIH exposure did not affect motor coordination, general locomotor activity, anxiety, or willingnessto explore. However, behavioral test results indicated that APP/PS1-CIH mice showed more spatial learning and memory deficits. CIH induced long-term potentiation (LTP) dysfunction of thehippocampusin WT mice. These effects were aggravated in APP/PS1 mice. The N-methyl-D-aspartic acid receptor (NMDAR) NR1 subunit and postsynaptic density 95 (PSD95) in the hippocampus of WT and APP/PS1 mice were downregulated. These findings showed that a postsynaptic mechanism was involved in the effect of CIH on cognitive impairment.

Cognitive impairment in Alzheimer's disease FAD4T mouse model: Synaptic loss facilitated by activated microglia via C1qA

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by cognitive dysfunction. The connection between neuroinflammation and abnormal synaptic function in AD is recognized, but the underlying mechanisms remain unclear. In this study, we utilized a mouse model of AD, FAD4T mice aged 6–7 months, to investigate the molecular changes affecting cognitive impairment. Behavior tests showed that FAD4T mice exhibited impaired spatial memory compared with their wild-type littermates. Immunofluorescence staining revealed the presence of Aβ plaques and abnormal glial cell activation as well as changes in microglial morphology in the cortex and hippocampus of FAD4T mice. Synaptic function was impaired in FAD4T mice. Patch clamp recordings of hippocampal neurons revealed reduced amplitude of miniature excitatory postsynaptic currents. Additionally, Golgi staining showed decreased dendritic spine density in the cortex and hippocampus of FAD4T mice, indicating aberrant synapse morphology. Moreover, hippocampal PSD-95 and NMDAR1 protein levels decreased in FAD4T mice. RNA-seq analysis revealed elevated expression of immune system and proinflammatory genes, including increased C1qA protein and mRNA levels, as well as higher expression of TNF-α and IL-18. Taken together, our findings suggest that excessive microglia activation mediated by complement factor C1qA may contribute to aberrant synaptic pruning, resulting in synapse loss and disrupted synaptic transmission, ultimately leading to AD pathogenesis and behavioral impairments in the FAD4T mouse model. Our study provides valuable insights into the underlying mechanisms of cognitive impairments and preliminarily explores a potentially effective treatment approach targeting on C1qA for AD.

Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. Synaptic dysfunction has appeared in the early stage of AD and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here we found upregulated Maf1 transcription factor in AD, and Maf1 conditional knockout in AD transgenic mice restored learning and memory function. Downregulation of Maf1 reduced intraneuronal Ca2+ concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulates the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodeling in neurons. Therefore, our results clarified the important role and mechanism of the Maf1-NMDAR1 signaling pathway in the stability of the synaptic structure, neuronal function, and behavior during the pathogenesis of AD, serving as a potential diagnostic and therapeutic target for the early onset of AD.

Testosterone deficiency worsens mitochondrial dysfunction in APP/PS1 mice.

Recent studies show testosterone (T) deficiency worsens cognitive impairment in Alzheimer's disease (AD) patients. Mitochondrial dysfunction, as an early event of AD, is becoming critical hallmark of AD pathogenesis. However, currently, whether T deficiency exacerbates mitochondrial dysfunction of men with AD remains unclear. The purpose of this study is to explore the effects of T deficiency on mitochondrial dysfunction of male AD mouse models and its potential mechanisms. Alzheimer's disease animal model with T deficiency was performed by castration to 3-month-old male APP/PS1 mice. Hippocampal mitochondrial function of mice was analyzed by spectrophotometry and flow cytometry. The gene expression levels related to mitochondrial biogenesis and mitochondrial dynamics were determined through quantitative real-time PCR (qPCR) and western blot analysis. SH-SY5Y cells treated with flutamide, T and/or H2O2 were processed for analyzing the potential mechanisms of T on mitochondrial dysfunction. Testosterone deficiency significantly aggravated the cognitive deficits and hippocampal pathologic damage of male APP/PS1 mice. These effects were consistent with exacerbated mitochondrial dysfunction by gonadectomy to male APP/PS1 mice, reflected by further increase in oxidative damage and decrease in mitochondrial membrane potential, complex IV activity and ATP levels. More importantly, T deficiency induced the exacerbation of compromised mitochondrial homeostasis in male APP/PS1 mice by exerting detrimental effects on mitochondrial biogenesis and mitochondrial dynamics at mRNA and protein level, leading to more defective mitochondria accumulated in the hippocampus. In vitro studies using SH-SY5Y cells validated T's protective effects on the H2O2-induced mitochondrial dysfunction, mitochondrial biogenesis impairment, and mitochondrial dynamics imbalance. Administering androgen receptor (AR) antagonist flutamide weakened the beneficial effects of T pretreatment on H2O2-treated SH-SY5Y cells, demonstrating a critical role of classical AR pathway in maintaining mitochondrial function. Testosterone deficiency exacerbates hippocampal mitochondrial dysfunction of male APP/PS1 mice by accumulating more defective mitochondria. Thus, appropriate T levels in the early stage of AD might be beneficial in delaying AD pathology by improving mitochondrial biogenesis and mitochondrial dynamics.

Association between clinical dementia rating and clinical outcomes in Alzheimer's disease.

We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI-Q]), and cognitive impairment in Alzheimer's disease (AD). We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR-global. Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI-Q scores increased steeply with MCI (NPI-Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI-Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). CDR-global staged AD by capturing differences in relevant outcomes along AD progression. There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages.

Rotating magnetic field inhibits Aβ protein aggregation and alleviates cognitive impairment in Alzheimer's disease mice

Rotating magnetic field inhibits Aβ protein aggregation and alleviates cognitive impairment in Alzheimer's disease mice