Age-related Alzheimer's Disease Research Articles

Drug Target to Alleviate Mitochondrial Dysfunctions in Alzheimer's Disease: Recent Advances and Therapeutic Implications.

Alzheimer's disease (AD) is a severe progressive neurodegenerative condition associated with neuronal damage and reduced cognitive function that primarily affects the aged worldwide. While there is increasing evidence suggesting that mitochondrial dysfunction is one of the most significant factors contributing to AD, its accurate pathobiology remains unclear. Mitochondrial bioenergetics and homeostasis are impaired and defected during AD pathogenesis. However, the potential of mutations in nuclear or mitochondrial DNA encoding mitochondrial constituents to cause mitochondrial dysfunction has been considered since it is one of the intracellular processes commonly compromised in early AD stages. Additionally, electron transport chain dysfunction and mitochondrial pathological protein interactions are related to mitochondrial dysfunction in AD. Many mitochondrial parameters decline during aging, causing an imbalance in reactive oxygen species (ROS) production, leading to oxidative stress in age-related AD. Moreover, neuroinflammation is another potential causative factor in AD-associated mitochondrial dysfunction. While several treatments targeting mitochondrial dysfunction have undergone preclinical studies, few have been successful in clinical trials. Therefore, this review discusses the molecular mechanisms and different therapeutic approaches for correcting mitochondrial dysfunction in AD, which have the potential to advance the future development of novel drug-based AD interventions.

Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid.

Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs. Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes. Four hundred nine DS adults (mean age=44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age. These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics. There is rapid increase in prevalence of amyloid beta (Aβ) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aβ PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aβ PET positivity and clinical symptom onset in DS.

Panax notoginseng saponins prevent dementia and oxidative stress in brains of SAMP8 mice by enhancing mitophagy

BackgroundMitochondrial dysfunction is one of the distinctive features of neurons in patients with Alzheimer’s disease (AD). Intraneuronal autophagosomes selectively phagocytose and degrade the damaged mitochondria, mitigating neuronal damage in AD. Panax notoginseng saponins (PNS) can effectively reduce oxidative stress and mitochondrial damage in the brain of animals with AD, but their exact mechanism of action is unknown.MethodsSenescence-accelerated mouse prone 8 (SAMP8) mice with age-related AD were treated with PNS for 8 weeks. The effects of PNS on learning and memory abilities, cerebral oxidative stress status, and hippocampus ultrastructure of mice were observed. Moreover, changes of the PTEN-induced putative kinase 1 (PINK1)-Parkin, which regulates ubiquitin-dependent mitophagy, and the recruit of downstream autophagy receptors were investigated.ResultsPNS attenuated cognitive dysfunction in SAMP8 mice in the Morris water maze test. PNS also enhanced glutathione peroxidase and superoxide dismutase activities, and increased glutathione levels by 25.92% and 45.55% while inhibiting 8-hydroxydeoxyguanosine by 27.74% and the malondialdehyde production by 34.02% in the brains of SAMP8 mice. Our observation revealed the promotion of mitophagy, which was accompanied by an increase in microtubule-associated protein 1 light chain 3 (LC3) mRNA and 70.00% increase of LC3-II/I protein ratio in the brain tissues of PNS-treated mice. PNS treatment increased Parkin mRNA and protein expression by 62.80% and 43.80%, while increasing the mRNA transcription and protein expression of mitophagic receptors such as optineurin, and nuclear dot protein 52.ConclusionPNS enhanced the PINK1/Parkin pathway and facilitated mitophagy in the hippocampus, thereby preventing cerebral oxidative stress in SAMP8 mice. This may be a mechanism contributing to the cognition-improvement effect of PNS.

Integrative Analysis of the Age-Related Dysregulated Genes Reveals an Inflammation and Immunity-Associated Regulatory Network in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease with a long incubation period. While extensive research has led to the construction of long non-coding RNA (lncRNA)-associated competing endogenous RNA (ceRNA) regulatory networks, which primarily derived from differential analyses between clinical AD patients and control individuals or mice, there remains a critical knowledge gap pertaining to the dynamic alterations in transcript expression profiles that occur with age, spanning from the pre-symptomatic stage to the onset of AD. In the present study, we examined the transcriptomic changes in AD model mice at three distinct stages: the unaffected (un-) stage, the pre-onset stage, and the late-onset stage, and identified 14, 57, and 99 differentially expressed mRNAs (DEmRs) in AD model mice at 3, 6, and 12months, respectively. Among these, we pinpointed 16 mRNAs closely associated with inflammation and immunity and excavated their lncRNA-mRNA regulatory network based on a comprehensive analysis. Notably, our preliminary analysis suggested that four lncRNAs (NONMMUT102943, ENSMUST00000160309, NONMMUT083044, and NONMMUT126468), eight miRNAs (miR-34a-5p, miR-22-5p, miR-302a/b-3p, miR-340-5p, miR-376a/b-5p, and miR-487b-5p), and four mRNAs (C1qa, Cd68, Ctss, and Slc11a1) may play pivotal roles in orchestrating immune and inflammatory responses during the early stages of AD. Our study has unveiled age-related AD risk genes, and provided an analytical framework for constructing lncRNA-mRNA networks using time series data and correlation analysis. Most notably, we have successfully constructed a comprehensive regulatory ceRNA network comprising genes intricately linked to inflammatory and immune functions in AD.

Basic Science and Pathogenesis - Part 1.

Neuropathologically, Alzheimer's disease (AD) is characterized by the presence of senile plaques composed of beta-amyloid (Aβ) and neurofibrillary tangles made of hyperphosphorylated tau. Aβ and p-tau have been shown to impact endoplasmic reticulum homeostasis, DNA damage response and autophagic functions. Intriguingly, alterations in these systems have also been connected to dysfunctions in UFMylation, a ubiquitin-like posttranslational modification. Analogous to ubiquitin, UFM1, is conjugated to substrates via a catalytic cascade involving UFM1-specific set of E1 (UBA5), E2 (UFC1), and a complex that consists of E3 ligase (UFL1), DDRGK1 and CDK5RAP3. UFMylation is reversible, and this is mediated by UFSP2. The UFMylation pathway is essential for brain development as complete loss of function of any of its components result in severe neurodevelopmental disorders. However, alterations in UFMylation and their role in and significance for age-related AD remains unknown. We performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2, tau, p-tau and other UFMylation pathway components in human post-mortem brain. Analyses were performed with RIPA- and 2% SDS-soluble fraction from frontal cortex. To validate our finding in human tissues, we knocked out UFM1 and UFSP2 in ReN cells, a neural progenitor cell model that has already been used to study AD and that can be terminally differentiated in neurons. We found a significant reduction of RIPA UFSP2, but an increase of RIPA and SDS UFM1 in AD compared to controls. Strikingly, RIPA UFSP2 had a strong negative correlation with both RIPA and SDS UFM1. Furthermore. UFM1 was significantly increased in UFSP2-KO neurons compared to WT, mirroring the negative correlation between UFM1 and UFSP2 observed in human brain. In addition, RIPA and SDS UFM1 had a strong positive correlation with p-tau, indicating that dysfunctional UFMylation might play an important role for disease pathogenesis. Reduction of RIPA soluble UFSP2 in human AD frontal cortex might result in the abnormal accumulation of UFM1 and this might further facilitate the AD pathogenesis. Because of its role for several central AD-relevant pathways, the UFMylation pathway might be a potential therapeutic target for AD.

Alzheimer's Disease and Aging Association: Identification and Validation of Related Genes.

Aging is considered a key risk factor for Alzheimer's disease (AD). This study aimed to identify and validate potential aging-related genes associated with AD using bioinformatics analysis. Datasets GSE36980 and GSE5281 were selected to screen differentially expressed genes (DEGs), and the immune cell correlation analysis and GSEA analysis of DEGs were performed. The intersection with senescence genes was taken as differentially expressed senescence-related genes (DESRGs), and the GSE44770 dataset was used for further validation. The potential biological functions and signaling pathways were determined by GO and KEGG, and the hub genes were identified by 12 algorithms in Cytohubba. The expression of 10 hub genes in different brain regions was determined and single-cell sequencing analysis was performed, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed. A total of 2137 DEGs were screened from the GSE36980 and GSE5281 datasets, and 278 SRGs were identified from the CellAge database. The overlapping DEGs and SRGs constituted 29 DESRGs, including 14 senescence suppressor genes and 15 senescence inducible genes. The top 10 hub genes, including MDH1, CKB, PSMD14, SMARCA4, PEBP1, DDB2, ITPKB, ATF7IP, YAP1, and EWSR1 were screened. Furthermore, four diagnostic genes were identified: PMSD14, PEBP1, ITPKB, and ATF7IP. The ROC analysis showed that the respective area under the curves (AUCs) of PMSD14, PEBP1, ITPKB, and ATF7IP were 0.732, 0.701, 0.747, and 0.703 in the GSE36980 dataset and 0.870, 0.817, 0.902, and 0.834 in the GSE5281 dataset. In the GSE44770 dataset, PMSD14 (AUC, 0.838) and ITPKB (AUC, 0.952) had very high diagnostic values in the early stage of AD. Finally, based on these diagnostic genes, we found that the drug Abemaciclib is a targeted drug for the treatment of age-related AD. Flutamide can aggravate aging-related AD. The results of this study suggest that cellular SRGs might play an important role in AD. PMSD14, PEBP1, ITPKB, and ATF7IP have the potential as specific biomarkers for the early diagnosis of AD.

Does self-directed learning address gaps in nursing student knowledge of Alzheimer’s disease?

ABSTRACT In the past two decades, deaths from stroke, heart disease and HIV decreased, whereas reported deaths from age-related Alzheimer’s disease (AD) have increased. Future nurses will be caring for the rapidly escalating number of older adults facing increased AD risk, yet nursing students’ knowledge has been shown to be limited regarding the age-related disease of Alzheimer’s (and the most common dementia type) (Aljezawi et al., 2022; Mattos et al., 2015). In this pilot study, a quasi-experimental approach was used to examine undergraduate baccalaureate nursing students’ basic knowledge about AD among two cohorts (N = 146). Testing occurred following an assigned self-directed learning activity as a means of providing the most current information regarding dementia. Pearson correlation and t-tests were applied in comparing student results in pre- and posttest surveys and investigating possible correlations between sociodemographic variables. Students in the 2020 group scored lower on ten of the thirty test items than the earlier 2018 cohort, suggesting that the method of self-directed learning, despite offering the most recent information, may be inadequate. To prepare nursing students to care for the increasing numbers of older adults at risk for Alzheimer’s disease, curricula that are inclusive of the most recent advances in science surrounding dementia-related illnesses, and supplemented by faculty lectures, is recommended. This requires faculty themselves to be knowledgeable of the most recent advances in dementia risk, prevention, detection and management.

GWAS of Genetic Resilience to Age‐Related Risk for Alzheimer’s Disease in Admixed African Ancestry Individuals

AbstractBackgroundWe sought to identify genetic variants that confer resilience to age‐related Alzheimer’s disease (AD) risk in subjects of admixed African ancestry.MethodsParticipants were ages 60+, of African ancestry (> = 25%), and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed, whole genome sequencing (WGS), or whole exome sequencing (WES). Genome‐wide association studies (GWAS) were performed per data type, split by Hispanic/non‐Hispanic participants (Table‐1), followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). GWAS performed multiple linear regression on an AD‐age score that models resilience to age‐related risk for AD (Le Guen & Belloy et al. 2021; Figure‐1). Models adjusted for sex, APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Brain amyloid Positron Emission Tomography (PET) qualitative reads together with SNP array data imputed to TOPMed were also available for African American individuals in A4. These data were independent from the primary GWAS and were used to evaluate significant GWAS variants for their association with binarized amyloid outcome (negative/positive), using a consistent model that additionally adjusted for age‐at‐scan.ResultsWe found a novel protective genome‐wide significant intergenic variant (rs77450754) ∼200kb downstream of ATXN8OS/KLHL1 (Figure‐2‐3). It has a MAF of 13% in African ancestry samples, but is rare (0.1%) in Europeans and (<2%) Latino/Admixed Americans in gnomAD v.3. The latter may explain why effects appeared less pronounced in the considered Hispanic samples (since linkage to potential causal nearby variants may differ) (Figure‐3). The variant also displayed a protective, non‐significant, association with brain amyloid in African ancestry samples (Table‐2). Interestingly, KLHL1, also known as MRP2, is a member of the superfamily of ATP‐binding cassette (ABC) transporters, and has potential functions related to neurite outgrowth and efflux transport at the blood‐brain barrier, supporting its potential relevance to AD pathogenesis.ConclusionsOur results provide new insights into genetic resilience to AD across aging and emphasize the importance of including ancestrally‐diverse populations in genetic studies. Our results also highlight the need for the field to compose ancestrally‐diverse multi‐omics and endophenotype data to support further validation analyses of genetic risk loci prioritized from GWAS.

Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at two different ages (3–4 vs. 10–11 months old). We quantitatively mapped the connectivity strengths of neural circuit inputs to hippocampal CA1 excitatory neurons from brain regions including hippocampal subregions, medial septum, subiculum and entorhinal cortex, comparing different age groups and genotypes. We focused on hippocampal CA1 because of its clear relationship with learning and memory and that the hippocampal formation shows clear neuropathological changes in human AD. Our results reveal alterations in circuit connectivity of hippocampal CA1 in AD model mice. Overall, we find weaker extrinsic CA1 input connectivity strengths in AD model mice compared with control mice, including sex differences of reduced subiculum to CA1 inputs in aged female AD mice compared with aged male AD mice. Unexpectedly, we find a connectivity pattern shift with an increased proportion of inputs from the CA3 region to CA1 excitatory neurons when comparing young and old AD model mice, as well as old wild-type mice and old AD model mice. These unexpected shifts in CA3-CA1 input proportions in this AD mouse model suggest the possibility that compensatory circuit increases may occur in response to connectivity losses in other parts of the hippocampal circuits. We expect that this work provides new insights into the neural circuit mechanisms of AD pathogenesis.

Pigmented and Dunkin‐Hartley Guinea Pigs as Natural Models for Brain Aging and Alzheimer’s Disease

Aging is the primary risk factor for most chronic diseases, including Alzheimer’s disease (AD). Current pre‐clinical approaches for studying brain aging and AD rely primarily on transgenic models intended to mirror pathologies associated with human brain aging and neurodegeneration (e.g., by increasing production of amyloid beta (Aβ) and phosphorylated tau). While these models may be useful, none completely mimic AD and its strong age‐dependence, and there has been limited success in translating pre‐clinical results and treatments to humans. We have characterized two non‐transgenic guinea pig strains (common ‘Pigmented’ guinea pigs and the Dunkin‐Hartley strain) that may be more useful models of brain aging and AD in this context. We show that these two models share many transcriptome features with both human brain aging and age‐related AD, especially with respect to biological processes like inflammation and transcriptional dysregulation. Additionally, both Pigmented and Dunkin‐Hartley animals exhibit age‐associated increases in numerous markers of human brain aging/AD, including neurofilament light chain (NfL, a marker of neuronal damage), S100 calcium‐binding protein B (S100ß, a marker of glial activation), ionized calcium‐binding adapter molecule 1 (Iba1, a marker of reactive microglia), and both Aβ and phosphorylated tau. These age‐associated effects are generally stronger in Dunkin‐Hartley animals, suggesting that this strain may be useful to model AD, while the Pigmented strain may be useful to model normal human brain aging.

Generation and characterization of a tractable C. elegans model of tauopathy.

Alzheimer's disease(AD) is an age-associated neurodegenerative disease that results in deterioration of memory and cognitive function. As a currently untreatable disorder, AD has emerged as one of the defining biomedical challenges of our time. Thus, new approaches that can examine the cellular and molecular mechanisms underlying age-related AD pathology are sorely needed. One of the hallmarks of Alzheimer's disease is the hyperphosphorylation of the tau protein. Caenorhabditis elegans have been previously used to study the genetic pathways impacted by tau proteotoxic stress; however, currently, available C. elegans tau models express the human protein solely in neurons, which are unresponsive to global RNA interference (RNAi). This limits powerful RNAi screening methods from being utilized effectively in these disease models. Our goal was to develop a C. elegans tau model that has pronounced tau-induced disease phenotypes in cells that can be modified by feeding RNAi methods. Towards this end, we generated a novel C. elegans transgenic line with codon-optimized human 0N4R V337M tau expressed in the body wall muscle under the myo-3 promoter. Immunoblotting experiments revealed that the expressed tau is phosphorylated on epitopes canonically associated with human AD pathology. The tau line has significantly reduced health metrics, including egg laying, growth rate, paralysis, thrashing frequency, crawling speed, and lifespan. These defects are suppressed by RNAi directed against the tau mRNA. Taken together, our results suggest that this alternative tau genetic model could be a useful tool for uncovering the mechanisms that influence the hyperphosphorylation and toxicity of human tau via RNAi screening and other approaches.

Changes in Biothiol Levels Are Closely Associated with Alzheimer's Disease.

Serum homocysteine (Hcy) level is considered to be an important biomarker for Alzheimer's disease (AD); however, the status of Hcy in brain tissue, and the association between brain and serum levels of Hcy in AD patients remain unclear. We aimed to examine whether the changes of three thiols are consistent in serum of AD patients and the brain of APP/PS1 mice, and to verify the effectiveness of Hcy as a biomarker for early AD detection. The levels of Hcy, cysteine (Cys), and glutathione (GSH) in Aβ1-42-treated PC12 cells, the brain and hippocampus of APP/PS1 mouse, and the serum of AD patients were evaluated using ethyl (E)-3-(9-chloro-11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f] pyrido [3,2,1 -ij] quinolin-10-yl)-2-cyanoacrylate (Probe 1) and ELISA assay or LC-MS. Measurement by Probe 1 revealed a significant increase in Hcy level, and a decrease in Cys and GSH levels in Aβ1-42-treated PC12 cells and the serum of AD patients. The hippocampus and whole brain of APP/PS1 mice also showed a significant increase in Hcy level alongside the accumulation of age-related AD symptoms. The upregulation of Hcy and the downregulation of Cys and GSH were reversed in the Aβ1-42-treated PC12 cells and the brain of APP/PS1 mice when supplemented with VB6. Changes in Hcy, Cys, and GSH levels in the brain of APP/PS1 mice and Aβ1-42-treated PC12 cells were observed in situ with a new fluorescent probe, which were consistent with the abnormal changes in Hcy, Cys, and GSH levels in the serum of AD patients. VB6 supplementation was successful in ameliorating abnormal increases in Hcy levels.

IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer's Disease Transgenic Mouse Model.

Aging is a major risk factor for Alzheimer’s disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ1–40/42 concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9–10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ1–40/42. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.

Pharmacological Treatment of Alzheimer's Disease: Insights from Drosophila melanogaster.

Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer’s disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular β-amyloid (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD.

Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner.

Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5-mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3-target replacement (TR) mice, not ApoE4-TR mice. It found that in aged ApoE3-TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4-TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3-TR and ApoE4-TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype-dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4- and age-related AD prevention and treatment.-Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner.

The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity.

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer’s disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.

Nursing students' knowledge about Alzheimer's disease.

Every 66 seconds a U.S. resident develops Alzheimer's disease (AD). Future nurses will be caring for the rapidly escalating number of adults turning 65, yet information regarding nursing students' knowledge about the age-related disease of Alzheimer's is limited. The purpose of this study was to examine 102 Florida baccalaureate nursing students' basic and advanced AD knowledge. A descriptive design using two AD knowledge measures and analysis using paired samples t-test were employed. Although the setting was a region of the U.S. with the highest percentage of older adults, knowledge deficits regarding age-related Alzheimer's disease were striking. Students' basic knowledge was significantly higher than their advanced AD knowledge (t(101) = 2.28, p = .027). Only 31% of students identified that high cholesterol may increase risk. Just 20% of students correctly answered that exercise does not prevent AD. About 25% correctly responded that the average life expectancy after the onset of AD is 6-12 years. Only 2% of nursing students correctly identified that persons with AD experience stress from disease-related symptoms. Overall, less than 50% of students correctly answered any item on the measure designed for use among health care providers. To better prepare nursing students to care for the increasing numbers of older adults facing risk of AD, updated curricula targeting dementia-related illnesses are essential. Information is offered regarding current state of the science resources of benefit to faculty, students, and practicing nurses, such as experiential learning and Hartford Institute of Geriatric Nursing collaborative programs.

Dietary Total Prenylflavonoids from the Fruits of Psoralea corylifolia L. Prevents Age-Related Cognitive Deficits and Down-Regulates Alzheimer's Markers in SAMP8 Mice.

Alzheimer’s disease (AD) is a serious threat for the aging society. In this study, we examined the preventive effect of the total prenylflavonoids (TPFB) prepared from the dried fruits of Psoralea corylifolia L., using an age-related AD mouse model SAMP8. We found that long-term dietary TPFB at 50 mg/kg·day significantly improved cognitive performance of the SAMP8 mice in Morris water maze tests, similar to 150 mg/kg·day of resveratrol, a popular neuro-protective compound. Furthermore, TPFB treatment showed significant improvements in various AD markers in SAMP8 brains, which were restored to near control levels of the normal mice, SAMR1. TPFB significantly reduced the level of amyloid β-peptide 42 (Aβ42), inhibited hyperphosphorylation of the microtubule-associated protein Tau, induced phosphorylation of Ser9 of the glycogen synthase kinase 3β (GSK-3β), and decreased the expression of the proinflammatory cytokines TNFα, IL-6, and IL-1β. Finally, TPFB also markedly reduced the level of serum derivatives of reactive oxygen metabolites (d-ROMs), a biomarker of oxidative stress in vivo. These results showed that dietary TPFB could effectively prevent age-related cognitive deficits and AD-like neurobiochemical changes, and may have a potential role in the prevention of Alzheimer’s disease.

Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing.

Seborrhoeic keratosis (SK) is an age-related skin disease. Amyloid precursor protein (APP) plays an important role in the pathogenesis of age-related Alzheimer's disease. The aim of this study was to elucidate the expression characteristics of APP in SK tissues (n = 50), and explore whether the production of APP is related to the onset of SK and skin ageing, including ultraviolet (UV)-induced ageing, as observed in normal skin (n = 79). The results of immunohistochemistry, Western blotting and quantitative real-time PCR showed that APP and its downstream products (i.e. amyloid-β42) were more highly expressed in SK than in paired adjacent normal skin tissues. In contrast, the expression of its key secretase (i.e. β-secretase1) was generally low. Furthermore, APP expression was higher in UV-exposed than non-exposed skin sites, and expression in the older age group (61-85 years) was greater than that in the younger age group (41-60 years) in SK tissues (p<0.05). APP expression correlated positively with age in epidermis (p<0.05), but not in dermis. These findings suggest that overexpression of APP may promote the onset of SK and is a marker of skin ageing and UV damage. Further research will elucidate whether therapeutic mitigation of increased levels of APP in the skin might delay the onset of SK and skin ageing.

Elucidating the link between the modifiable risk factors of Alzheimer's disease and neuroinflammation.

Increased worldwide longevity through medical interventions, although beneficial, has allowed the age-related Alzheimer's disease (AD) to become an epidemic of the 21st century. AD pathology involves adverse activation of microglia, the immune cells of the brain and resulting chronic neuroinflammation. Certain diets, physical inactivity and Type 2 diabetes mellitus have been identified as the risk factors for developing AD, which may increase the risk of AD by neuroimmune mechanisms primarily through the overactivation of microglia. Thus, modifying these risk factors may represent an alternative therapeutic strategy for lowering the incidence of AD. We highlight the link between select modifiable risk factors and neuroimmune mechanisms, and demonstrate that by controlling microglial activation and neuroinflammation the prevalence of AD may be decreased.