Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

Strategies for translating proteomics discoveries into drug discovery for dementia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis

Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.

Tau truncation in the pathogenesis of Alzheimer's disease:a narrative review

Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.

中等强度有氧运动对Alzheimer's病干预效果的分析

目的探讨Alzheimer's病(AD)患者中等强度有氧运动干预的效果及其影响因素。方法将98例AD患者随机分为运动组(50例)和对照组(48例),运动组接受3个月中等强度有氧训练,分别在基线、3个月、6个月利用MMSE、AD评定量表-认知量表(ADAS-cog)评估认知功能,AD协作研究-日常生活能力评估量表(ADCS-ADL)评估日常生活能力,神经精神量表(NPI)评估精神行为症状,老年性痴呆生活质量量表(QOL-AD)评估生活质量。以ADAS-cog评分3个月与基线时差值(ADAS-cog3-0)为因变量通过多因素线性回归分析患者基线特征是否会影响运动的疗效。将ADAS-cog3-0改善≥4分的患者纳入预后良好组,其他则纳入非预后良好组,将多因素线性回归分析中P<0.05的变量纳入逻辑回归进行分析,通过ROC曲线确定最佳分界值。结果与对照组相比,运动组在3个月和6个月时MMSE、QOL-AD评分显著升高,ADAS-cog评分显著降低(均P<0.05);在3个月时ADCS-ADL评分显著升高,NPI评分显著下降(均P<0.05);在6个月时,ADCS-ADL、NPI评分与对照组比较差异无统计学意义。回归分析显示,基线时MMSE评分对运动组认知功能改善有负性影响,而年龄、性别、教育水平、缺血症状、基线时日常生活能力、精神行为症状、生活质量对其没有影响。敏感、特异性分析显示,以MMSE>21.5分为界,界内的AD患者有氧运动效果好。结论有氧运动对AD患者的认知功能、日常生活能力、精神行为症状、生活质量均有明显改善作用,且认知水平越保留的AD患者,有氧运动对其近期作用越好。

SIRT2 as a potential new therapeutic target for Alzheimer's disease

Alzheimer's disease is the most common cause of dementia globally with an increasing incidence over the years,bringing a heavy burden to individuals and society due to the lack of an effective treatment.In this context,sirtuin 2,the sirtuin with the highest expression in the brain,has emerged as a potential therapeutic target for neurodegenerative diseases.This review summarizes and discusses the complex roles of sirtuin 2 in different molecular mechanisms involved in Alzheimer's disease such as amyloid and tau pathology,microtubule stability,neuroinflammation,myelin formation,autophagy,and oxidative stress.The role of sirtuin 2 in all these processes highlights its potential implication in the etiology and development of Alzheimer's disease.However,its presence in different cell types and its enormous variety of substrates leads to apparently contra dictory conclusions when it comes to understanding its specific functions.Further studies in sirtuin 2 research with selective sirtuin2 modulators targeting specific sirtuin 2 substrates are necessary to clarify its specific functions under different conditions and to validate it as a novel pharmacological target.This will contribute to the development of new treatment strategies,not only for Alzheimer's disease but also for other neurodegenerative diseases.

Biomaterials-based anti-inflammatory treatment strategies for Alzheimer's disease

The current therapeutic drugs for Alzheimer's disease only improve symptoms,they do not delay disease progression.Therefo re,there is an urgent need for new effective drugs.The underlying pathogenic factors of Alzheimer's disease are not clear,but neuroinflammation can link various hypotheses of Alzheimer's disease;hence,targeting neuroinflammation may be a new hope for Alzheimer's disease treatment.Inhibiting inflammation can restore neuronal function,promote neuro regeneration,reduce the pathological burden of Alzheimer's disease,and improve or even reverse symptoms of Alzheimer's disease.This review focuses on the relationship between inflammation and various pathological hypotheses of Alzheimer's disease;reports the mechanisms and characteristics of small-molecule drugs(e.g.,nonsteroidal anti-inflammatory drugs,neurosteroids,and plant extracts);macromolecule drugs(e.g.,peptides,proteins,and gene therapeutics);and nanocarriers(e.g.,lipid-based nanoparticles,polymeric nanoparticles,nanoemulsions,and inorganic nanoparticles)in the treatment of Alzheimer's disease.The review also makes recommendations for the prospective development of anti-inflammatory strategies based on nanocarriers for the treatment of Alzheimer's disease.

Altered synaptic currents,mitophagy,mitochondrial dynamics in Alzheimer's disease models and therapeutic potential of Dengzhan Shengmai capsules intervention

Emerging research suggests a potential association of progression of Alzheimer's disease(AD)with alterations in synaptic currents and mitochondrial dynamics.However,the specific associations between these pathological changes remain unclear.In this study,we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models.The investigations included behavioural tests,brain magnetic resonance imaging(MRI),liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis,Nissl staining,thioflavin-S staining,enzyme-linked immunosorbent assay,Golgi-Cox staining,transmission electron microscopy(TEM),immunofluorescence staining,proteomics,adenosine triphosphate(ATP)detection,mitochondrial membrane potential(MMP)and reactive oxygen species(ROS)assessment,mitochondrial morphology analysis,electrophysiological studies,Western blotting,and molecular docking.The results revealed changes in synaptic currents,mitophagy,and mitochondrial dynamics in the AD models.Remarkably,intervention with Dengzhan Shengmai(DZSM)capsules emerged as a pivotal element in this investigation.Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention,which notably amplified the frequency and amplitude of synaptic transmission.The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions,including the hippocampal CA3,primary cingular cortex,prelimbic system,and dysgranular insular cortex.DZSM intervention led to increased IDE levels,augmented long-term potential(LTP)amplitude,and enhanced dendritic spine density and length.Moreover,DZSM intervention led to favourable changes in mitochondrial parameters,including ROS expression,MMP and ATP contents,and mitochondrial morphology.In conclusion,our findings delved into the realm of altered synaptic currents,mitophagy,and mitochondrial dynamics in AD,concurrently highlighting the therapeutic potential of DZSM intervention.

Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease

Alzheimer's disease(AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low-and middle-income countries.

Searching for new drugs to treat Alzheimer’s disease dementia through multiple pathways

Dementia is a group of diseases,including Alzheimer's disease(AD),vascular dementia,Lewy body dementia,frontotemporal dementia,Parkinson's disease dementia,metabolic dementia and toxic dementia.The treatment of dementia mainly includes symptomatic treatment by controlling the primary disease and accompanying symptoms,nutritional support therapy for repairing nerve cells,psychological auxiliary treatment,and treatment that improves cognitive function through drugs.Among them,drug therapy to improve cognitive function is important.This review focuses on introducing and commenting on some recent progress in exploring drugs to improve cognitive function,especially the new progress in drug treatment for AD.We mainly discuss the opportunities and challenges in finding and developing new therapeutic drugs from the aspects of acetylcholinesterase,N-methyl-D-aspartate glutamate receptor,amyloid protein,tau protein and chronic immune inflammation.

Alzheimer's disease with depressive symptoms: Clinical effect of intermittent theta burst stimulation repetitive transcranial magnetic stimulation

BACKGROUND Alzheimer's disease(AD),characterized by the ongoing deterioration of neural function,often presents alongside depressive features and greatly affects the quality of life of individuals living with the condition.Although several treatment methods exist,their efficacy is limited.In recent years,repetitive transcranial magnetic stimulation(rTMS)utilizing the theta burst stimulation(TBS)mode,specifically the intermittent TBS(iTBS),has demonstrated promising therapeutic potential in the management of neuropsychiatric disorders.AIM To examine the therapeutic efficacy of iTBS mode of rTMS for treating depressive symptoms in patients with AD.METHODS This retrospective study enrolled 105 individuals diagnosed with AD with depressive symptoms at Huzhou Third Municipal Hospital,affiliated with Huzhou University,between January 2020 and December 2023.Participants received standard pharmacological interventions and were categorized into control(n=53)and observation(n=52)groups based on treatment protocols.The observation group received iTBS mode of rTMS,while the control group received pseudo-stimulation.A comparative analysis evaluated psychological well-being,adverse events,and therapeutic at initiation of hospitalization(T0)and 15 days post-treatment(T1).RESULTS At T1,both groups exhibited a marked reduction in self-rating depression scale and Hamilton depression scale scores compared to T0.Furthermore,the observa-tion group showed a more pronounced decrease than the control group.By T1,the Mini-mental state examination scores for both groups had increased markedly from their initial T0 assessments.Importantly,the increase was particularly more substantial in the observation group than in the control group.Fourteen patients in the control group had ineffective treatment effects,while five patients in the observation group experienced the same.Additionally,the observation group experienced a substantially reduced incidence of ineffective treatment as compared to the control group(both P<0.05);there were no recorded serious adverse events in either group.CONCLUSION The iTBS model of rTMS effectively treated AD with depression,improving depressive symptoms and cognitive function in patients without serious adverse reactions,warranting clinical consideration.

Effectiveness of Music-Based Therapeutic Intervention on People with Dementia: A Rapid Review

Background: Dementia is a condition with progressive cognitive dysfunction and manifestation of both behavioral and psychosocial symptoms. Non-pharmacological measures such as music therapy are gaining importance since efficacy and safety of people with dementia have been questionable for pharmacological measures. Patient’s response to music is persistent even in the later stage of dementia. Aim: This rapid review aims to identify, analyze, evaluate, and summarize the best available evidence on the effectiveness of music-based therapeutic interventions among people with dementia. Method: CINAHL Cochrane Library, internet websites of rapid review producers, and reference lists were searched to identify articles for inclusion. Two reviewers independently screened the literature search results. Effectiveness, music-based therapeutic intervention, dementia, Alzheimer’s disease, systematic review and systematic review with meta-analysis terms were used to abstract data from included studies. Main Findings: 11 SRs and SRs with meta-analysis were reviewed which revealed positive effect of music therapy on five major outcomes with 9 studies effect on behavioral outcome, 6 studies with positive effect on psychosocial outcome reducing anxiety, 6 with improved cognition, 1 study revealed with improved quality of life and 1 study revealed effect on physiological outcomes. Conclusion: Music therapy has positive effect on treatment of dementia but further studies with larger sample size and specified to single intervention should be conducted to provide generalisable and precise results on this topic.

Human immunodeficiency virus-associated dementia complex with positive 14-3-3 protein in cerebrospinal fluid:A case report

BACKGROUND Human immunodeficiency virus(HIV)-associated dementia(HAD)is a subcortical form of dementia characterized by memory deficits and psychomotor slowing.However,HAD often presents with symptoms similar to those of Creutzfeldt-Jakob disease(CJD),particularly in patients with acquired immune deficiency syndrome(AIDS).CASE SUMMARY We report the case of a 54-year-old male who exhibited cognitive dysfunction and secondary behavioral changes following HIV infection and suspected prion exposure.The patient was diagnosed with HIV during hospitalization and his cerebrospinal fluid tested positive for 14-3-3 proteins.His electroencephalogram showed a borderline-abnormal periodic triphasic wave pattern.Contrast-enhanced magnetic resonance imaging revealed moderate encephalatrophy and demyelination.Initially,symptomatic treatment and administration of amantadine were pursued for presumed CJD,but the patient’s condition continued to deteriorate.By contrast,the patient’s condition improved following anti-HIV therapy.This individual is also the only patient with this prognosis to have survived over 4 years.Thus,the diagnosis was revised to HAD.CONCLUSION In the diagnostic process of rapidly progressive dementia,it is crucial to rule out as many potential causes as possible and to consider an autopsy to diminish diagnostic uncertainty.The 14-3-3 protein should not be regarded as the definitive marker for CJD.Comprehensive laboratory screening for infectious diseases is essential to enhance diagnostic precision,especially in AIDS patients with potential CJD.Ultimately,a trial of diagnostic treatment may be considered when additional testing is not feasible.

Causal relationships between gut microbiota and dementia:A twosample,bidirectional,Mendelian randomization study

BACKGROUND Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia,including Alzheimer's dementia,vascular dementia,and dementia in other diseases classified elsewhere.However,the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear.AIM To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization(MR)analysis.METHODS A bidirectional,two-sample,MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study(GWAS)summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium.Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F-statistic.Five MR methods were employed,and the robustness of our findings was validated.To account for multiple comparisons,we applied the Bonferroni method for P-value adjustment.RESULTS We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes,potentially serving as risk or protective factors for the disease.In addition,reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes.An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy.After applying correction for multiple testing,we observed that the order Bacillales(odds ratio:0.830,95%confidence interval:0.740-0.932,P=0.00155,Padjust=0.0311)exhibited a strong association with Alzheimer’s disease-related dementia.CONCLUSION The results suggest that gut microbiota is causally associated with dementia.Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.

An Innovative Person-Centered Model for Provision of Mental, Social and Medical Care for People Living with Dementia

Globally there is an increased digitalization going on with an increasing number of people having access to the internet, having smartphones and now also in many countries being expected to access health-related information and schedule appointments through websites, apps or web-based portals. Healthcare providers have also adopted this with an increasing number of public or private organizations providing web-based portals as well as app interfaces to some of the largest electronic healthcare systems. The benefit of this is easier access, more efficient provision of services, increased transparency and improved workflows. This may increase the population’s capability to manage their conditions and reduce the contacts to, thereby burdening healthcare professionals. But not all will be able to benefit from this digital (r)evolution. Those who will not be able to include people with dementia. For people with dementia to also be able to take advantage of digital health tools and services, it will require planning and involvement of caregivers. In 2017, we presented the Epital Care Model as a framework to organize an efficient people-centered cross-disciplinary and cross-sectoral way to organize activities, roles, responsibilities and describe geographical locations and used technologies in response to individuals’ specific diagnoses and everyday changes in their condition. In 2021, an EU-funded project was initiated to investigate how living labs and scaling up could be done building upon the ECM. One of the living labs was organized around an organization providing care to PWD in Netherlands. In the period 2021 to 2024, we have tried to identify ways for how the ECM could be used to digitally enable the services provided by the organization. In 2022, the care organization tanteLouise started a project originally named Daycare Centre2.0 (now called “Van Thuis Uit” meaning “From Home”), together with healthcare insurance company CZ, and developed a model for onboarding people with dementia and introducing them to specific interventions based on their personal goals and needs. We here present how the ECM and the “Van Thuis Uit” can be mapped within each other to create synergy in creating a healthcare setting for people with dementia. This work may serve as a model for other conditions, where individuals are likely to need more intensive support from their informal caregivers due to a relatively rapid progression of the condition or development of severe impairments. Examples here can be neurologic conditions such as multiple sclerosis and amyotrophic lateral sclerosis or the final stage of conditions that require palliation.

The complex effects of miR-146a in the pathogenesis of Alzheimer's disease

Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities.Neuroinflammatory plaques formed through the extracellular deposition of amyloid-βproteins,as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins,comprise two typical pathological features of Alzheimer's disease.Besides symptomatic treatment,there are no effective therapies for delaying Alzheimer's disease progression.MicroRNAs(miR)are small,non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes.Indeed,miR-146a,a NF-κB-regulated gene,has been extensively implicated in the development of Alzheimer's disease through several pathways.Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder.Mi R-146a is believed to reduce amyloid-βdeposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway;however,there is also evidence supporting that it can promote these processes through many other pathways,thus exacerbating the pathological manifestations of Alzheimer's disease.It has been widely reported that miR-146a mediates synaptic dysfunction,mitochondrial dysfunction,and neuronal death by targeting m RNAs encoding synapticrelated proteins,mitochondrial-related proteins,and membrane proteins,as well as other mRNAs.Regarding the impact on glial cells,miR-146a also exhibits differential effects.On one hand,it causes widespread and sustained inflammation through certain pathways,while on the other hand,it can reverse the polarization of astrocytes and microglia,alleviate neuroinflammation,and promote oligodendrocyte progenitor cell differentiation,thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons.In this review,we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer's disease.We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer's disease,such as amyloid-βdeposition,tau protein hyperphosphorylation,neuronal death,mitochondrial dysfunction,synaptic dysfunction,and glial cell dysfunction,as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer's disease.

Characterization of cerebrovascular changes in Alzheimer's disease mice by photoacoustic imaging

The cerebral vasculature plays a significant role in the development of Alzheimer's disease(AD),however,the specific association between them remains unclear.In this paper,based on the benefits of photoacoustic imaging(PAI),including label-free,high-resolution,in vivo imaging of vessels,we investigated the structural changes of cerebral vascular in wild-type(WT)mice and AD mice at different ages,analyzed the characteristics of the vascular in different brain regions,and correlated vascular characteristics with cognitive behaviors.The results showed that vascular density and vascular branching index in the cortical and frontal regions of both WT and AD mice decreased with age.Meanwhile,vascular lacunarity increased with age,and the changes in vascular structure were more pronounced in AD mice.The trend of vascular dysfunction aligns with the worsening cognitive dysfunction as the disease progresses.Here,we utilized in vivo PAI to analyze the changes in vascular structure during the progression of AD,elucidating the spatial and temporal correlation with cognitive impairment,which will provide more intuitive data for the study of the correlation between cerebrovascular and the development of AD.

The roles of RACK1 in the pathogenesis of Alzheimer's disease

The receptor for activated C kinase 1(RACK1)is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease(AD),a prevalent neurodegenerative disease.RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD.Specifically,RACK1 is involved in regulation of the amyloid-β precursor protein processing through α-or β-secretase by binding to different protein kinase C isoforms.Additionally,RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors,thereby preventing neuronal excitotoxicity.RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways,such as nuclear factor-kappa B,tumor necrosis factor-alpha,and NOD-like receptor family pyrin domain-containing 3 pathways.The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy,in which RACK1 is a potential target.In this review,we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.

The Alzheimer’s Dementia Patients’ Observed Illness Course and Experience in Ghana and Care Lessons to Be Learnt: A Mental Health Professional’s Perspective

Alzheimer’s disease (AD) and associated dementia patient numbers continue to increase globally with associated economic costs to healthcare systems. Of note is the increase in numbers in lower and middle-income countries (LMICs) including Sub-Saharan African (SSA) countries, which already face challenges with their health budgets from communicable and non-communicable diseases. Ghana, an SSA country, faces the problem of healthcare budgetary difficulties and the additional impact of AD as a consequence of increasing population strata of old aged persons (OAPs) due to the demographic transition effect. This article uses examples of known patients’ illness courses to give a perspective on the lived experience of patients with dementia (PWD) in Ghana, living amongst a populace with a culture of stigmatization of PWD, and a relatively fragile public mental health system (PMHS) for those with mental illness, including AD. The lived experience of AD patients is characterised by stigmatisation, discrimination, non-inclusiveness, diminished dignity and human rights abuses in the face of their mental disability, and eventually death. This article is an advocacy article giving voice to the voiceless and all persons suffering from AD and other dementias in Ghana, whilst pleading for a call to action from healthcare professionals and responsible state agencies.