Increased Amyloid Precursor Protein Research Articles

The Role of Copper in Alzheimer's Disease Etiopathogenesis: An Updated Systematic Review.

Alzheimer's disease (AD) is the most common cause of dementia and cognitive decline in the elderly. Although the etiology of AD is unknow, an increase in amyloid precursor protein (APP) leads to the toxic aggregation of Aβ plaques. Several factors, such as hypertension, diabetes, dyslipidemia, smoking, hormonal changes, and metal exposure, could increase the risk of developing AD. In this review, we will examine the role of copper (Cu) in the pathophysiology of AD, as well as the mechanisms involved in neurotoxicity and cognitive decline. This review was conducted in accordance with PRISMA guidelines. We performed a comprehensive literature analysis over the last ten years on AD and Cu. Only late-onset Alzheimer's disease was considered; only studies on elderly people of both sexes were included. A total of seven articles were picked for this review, three studies focused on non-ceruloplasmin-bound Copper (non-Cp-Cu) and four on ceruloplasmin-bound Copper (Cp-Cu). The results showed higher Cu concentrations in patients compared to healthy controls. Elevated concentrations of Cu may contribute to the progression of AD, potentially interacting with ATP7B mutations, oxidative stress (OS), and amyloid-β plaques. Future research is needed to provide more robust evidence and better characterize the relationship between AD and Cu.

Comparison between sub-chronic and chronic sleep deprivation-induced behavioral and neuroimmunological abnormalities in mice: Focusing on glial cell phenotype polarization

BackgroundSleep disorders, depression, and Alzheimer’s disease (AD) are extensively reported as comorbidity. Although neuroinflammation triggered by microglial phenotype M1 activation, leading to neurotransmitter dysfunction and Aβ aggregation, is considered as the leading cause of depression and AD, whether and how sub-chronic or chronic sleep deprivation (SD) contribute to the onset and development of these diseases remains unclear. MethodsMemory and depression-like behaviors were evaluated in both SDs, and then circadian markers, glial cell phenotype polarization, cytokines, depression-related neurotransmitters, and AD-related gene/protein expressions were measured by qRT-PCR, enzyme-linked immunosorbent assay, high-performance liquid chromatography, and western-blotting respectively. ResultsBoth SDs induced give-up behavior and anhedonia and increased circadian marker period circadian regulator 2 (PER2) expression, which were much worse in chronic than in the sub-chronic SD group, while brain and muscle ARNT-like protein-1 only decreased in the chronic-SD. Furthermore, increased microglial M1 and astrocyte A1 expression and proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α was observed in both SDs, which were more significant in chronic SD. Similarly, decreased norepinephrine and 5-hydroxytryptamine/5-hydroxyindoleacetic acid ratio were more significant, which corresponds to the worse depression-like behavior in chronic than sub-chronic-SD. With regard to AD, increased amyloid precursor protein (APP) and soluble (s)-APPβ and decreased sAPPα in both SDs were more significant in the chronic. However, sAPPα/sAPPβ ratio was only decreased in chronic SD. ConclusionThese findings suggest that both SDs induce depression-like changes by increasing PER2, leading to neuroinflammation and neurotransmitter dysfunction. However, only chronic SD induced memory impairment likely due to severer circadian disruption, higher neuroinflammation, and dysregulation of APP metabolism

The Tao Hong Si Wu Decoction ameliorates diabetes-associated cognitive dysfunction by inhibiting the formation of amyloid plaques.

The herbs in Tao Hong Si Wu Decoction (THSWD) are beneficial in the treatment of cognitive impairment. However, the underlying mechanisms of THSWD in treating diabetes-associated cognitive dysfunction (DACD) are not entirely explored. This study is aimed to investigate the therapeutic effects of THSWD in DACD model rats and the underlying mechanism. Ultra-high-phase liquid chromatography was employed to identify the main compounds contained in the THSWD extract. DACD rat model was induced by feeding with a high-sugar and high-fat diet and injecting streptozotocin (35mg/kg). DACD rats were gavaged with THSWD for 1week. The learning and memory abilities of the rats were measured by using the Morris water maze. Western blotting was used to detect the changes in DACD rat targets. Statistical methods were used to evaluate the correlation between proteins. The results show that THSWD effectively reduced the escape latency, hippocampal neuron damage, glycosylated hemoglobin, type A1C, and blood lipid levels in DACD rats. Furthermore, DACD rats showed significantly increased amyloid precursor protein, β-secretase, Aβ1-40 , Aβ1-42 , Tau phosphorylation, and advanced glycation end products (AGEs) expression. However, THSWD treatment can reverse this phenomenon. THSWD can improve the learning and memory abilities of DACD rats by inhibiting the expression of AEGs-AGE receptors pathway, which provides an experimental basis for the clinical application of THSWD. In addition, the experiment combines pharmacological and statistical methods, which offers a new perspective for the study of Chinese herbal medicine.

Effects of γ‐secretase modulator BPN‐15606 in amyloidogenic responses to air pollution in mouse cortex

AbstractBackgroundEpidemiological studies show chronic exposure to air pollution accelerates cognitive decline and increase AD risk. In mouse models, brain accumulation of amyloid beta (Aβ) is enhanced by air pollution. Pharmacological approaches show benefit of γ‐secretase modulation (GSM; BPN‐15606), decreasing Aβ42 and amyloid plaques in mouse brain. We hypothesize that GSM will limit Aβ42 production during air pollution exposure in the diesel exhaust particle (DEP) model.MethodC57BL/6 mice were exposed to DEP for 8 weeks. DEP from National Institute of Science and Technology (NIST 2975) was suspended in water and re‐aerosolized for 5 hr/day at concentration of 100 µg/m3. GSM was mixed into chow (10mg/day dose). Experimental groups were filtered air (FA), DEP, FA+GSM, and DEP+GSM; proteins from soluble fraction of cerebral cortex were analyzed by immunoblots.ResultGSM alone increased amyloid precursor protein (APP) and the Aβ38 peptide. Air pollution (DEP) increased APP, with no further change in DEP+GSM. PSEN1, key enzyme for γ‐secretase function, decreased with DEP+GSM, along with the Aβ42 peptide and the Aβ42/40 ratio.ConclusionDuring exposure to DEP, GSM decreased Aβ42 and the ratio of Aβ42/40. These results suggest that γ‐secretase modulation is beneficial during air pollution, preventing Aβ42 increases.

334 AMYLOID-BETA 1-40 AND DAPT IN ACUTE MYOCARDIAL INFARCTION

Abstract Background Atherosclerotic plaque destabilization and platelet activation is a prompt and progressive process that is the basis of acute coronary syndromes (ACS). Amyloid-β 1-40 (Aβ (1-40)), is highly expressed in atherosclerotic plaques and is released in plasma by activated platelets. Some animal studies suggested that an increase in amyloid precursor protein (sAPP770) levels upon atherosclerotic plaque activation, anticipates myocardial injury. Platelets inhibition is the keystone in the management of patients with ACS, but the data regarding the benefits of Dual Antiplatelet Therapy (DAPT) before coronary angiography is still disputed. Methods In a large prospective cohort of 1038 patients hospitalized for AMI (both STEMI 702 /NSTEMI 333 patients), we evaluated the impact of DAPT on Aβ (1-40) levels, the correlation with inflammatory biomarkers, and Aβ (1-40) prognostic value on long-term mortality. Results The median concentration of Aβ (1-40) in plasma at admission was 90.47 (54.49-130.47) pg/ml. At hospital admission patients on DAPT had significantly lower levels of Aβ (1-40) compared to patients receiving only aspirin (67.56 (42.7-120.23) pg/ml vs. 92.25 (56.16-131.17) pg/ml, p=0.004), independently of patients’ gender or diagnosis STEMI/NSTEMI. Aβ (1-40) positively correlated with older age and higher levels of CRP and TNFα. There was no significant difference among patients who received DAPT therapy and those who did not towards age, presence of chronic renal failure, hypertension, nor in the rate of revascularization procedures (both percutaneous coronary intervention and bypass). Kaplan-Meier analysis showed that higher Aβ ​​(1-40) levels during the 49-month follow-up were associated with higher mortality risk (p<0.0001). Also, at multivariate Cox regression analysis Aβ ​​(1-40) level (HR =1.003 (95% CI, 1.001-1.005), p=0.017 was predictive for mortality, together with older age, higher interleukin (Il)-1β, worse left ventricular systolic function, and GFR ≤ 60 mL/min. Conclusions STEMI/NSTEMI patients receiving DAPT at hospital admission, have a significantly lower plasma concentration of Aβ (1-40), which is an independent predictor of long-term mortality.

The Fundamental Role of Neuroinflammation at the Beginning and Progression of Alzheimer’s Disease

The majority of astrocytes are responsible for the expression and release of S100B, a 21-kDa calcium-binding protein of the EFhand type (helix E-loop-helix F). It is mostly present in the neurological system and, depending on concentration, has different (beneficial, detrimental) effects on neurons, astrocytes, and microglia. an effect on the survival and development of both glia and neuronal cells. Patients with Down Syndrome and Alzheimer's Disease (AD) have brains that are overexpressed with the S100 protein Down Syndrome (DS). Increased S100B concentrations are linked to brain trauma and ischemia, most likely due to astrocyte destruction. As S100B appears to influence multiple neuropathological mechanisms in (AD) , a pivotal role for S100B as a significant contributor to (AD) pathology has emerged. Studies of S100B overexpression, S100B localization, multiple relationships between S100B and increase amyloid precursor protein, the interaction between S100B and dystrophic neuritis plaques, and change in a neurofibrillary tangle in Alzheimer's disease focus on providing evidence for the involvement of S100B in Alzheimer's disease pathology and neuronal loss. The significance of S100B in head trauma and degenerative brain disease is the central subject of this review. Overexpressing s100B, which also causes more astrogliosis and microgliosis, speeds up the pathogenesis of Alzheimer's disease. Numerous clinical problems have been associated with an increase in S100B, a neurotropic signaling protein.

MiR-702-5p ameliorates diabetic encephalopathy in db/db mice by regulating 12/15-LOX

The purpose of this study was to investigate the effect of miR-702-5p on diabetic encephalopathy (DE) and the interaction of miR-702-5p/12/15-LOX in the central nervous system (CNS). In this study, db/db mice were used as DE animal model and HT22 cells were treated with high-glucose (HG). Based on the bioinformatics prediction of possible binding sites between miR-702-5p and 12/15-LOX, we found that the expression of miR-702-5p was significantly down-regulated while 12/15-LOX up-regulated in vivo and in vitro, and the expression changes were inversely correlated. In vivo, diabetic mice with cognitive dysfunction and hippocampal neuronal damage had a concomitant increase in amyloid precursor protein (APP), amyloid beta(Aβ), tau, BAX protein expressions; by contrast, Bcl-2 protein expression was significantly decreased. Overexpression of miR-702-5p significantly reduced the histopathological damage of the hippocampus, improved the learning and memory function of db/db mice, down-regulated 12/15-LOX, APP, Aβ, tau, BAX protein expressions significantly and up-regulated the expression of Bcl-2. In vitro, miR-702-5p mimic reversed the decline in cell viability and the increase in cell apoptosis induced by HG. Simultaneously, reduced 12/15-LOX, APP, Aβ, BAX protein expressions, and increased Bcl-2 protein expression were detected in the miR-702-5p mimic group. Moreover, combined administration of miR-702-5p mimic and 12/15-LOX overexpression lentivirus significantly reversed the protective effect of up-regulation of miR-702-5p. In conclusion, miR-702-5p has a neuroprotective effect on DE, and this effect was achieved by inhibiting 12/15-LOX. However, miR-702-5p had an endogenous regulatory effect on 12/15-LOX rather than a direct targeting relationship.

Altered amyloid precursor protein, tau-regulatory proteins, neuronal numbers and behaviour, but no tau pathology, synaptic and inflammatory changes or memory deficits, at 1month following repetitive mild traumatic brain injury.

Repetitive mild traumatic brain injury, commonly experienced following sports injuries, results in various secondary injury processes and is increasingly recognised as a risk factor for the development of neurodegenerative conditions such as chronic traumatic encephalopathy, which is characterised by tau pathology. We aimed to characterise the underlying pathological mechanisms that might contribute to the onset of neurodegeneration and behavioural changes in the less-explored subacute (1-month) period following single or repetitive controlled cortical impact injury (five impacts, 48 h apart) in 12-week-old male and female C57Bl6 mice. We conducted motor and cognitive testing, extensively characterised the status of tau and its regulatory proteins via western blot and quantified neuronal populations using stereology. We report that r-mTBI resulted in neurobehavioural deficits, gait impairments and anxiety-like behaviour at 1 month post-injury, effects not seen following a single injury. R-mTBI caused a significant increase in amyloid precursor protein, an increased trend towards tau phosphorylation and significant changes in kinase/phosphatase proteins that may promote a downstream increase in tau phosphorylation, but no changes in synaptic or neuroinflammatory markers. Lastly, we report neuronal loss in various brain regions following both single and repeat injuries. We demonstrate herein that repeated impacts are required to promote the initiation of a cascade of biochemical events that are consistent with the onset of neurodegeneration subacutely post-injury. Identifying the timeframe in which these changes occur and the pathological mechanisms involved will be crucial for the development of future therapeutics to prevent the onset or mitigate the progression of neurodegeneration following r-mTBI.

A dual potassium channelopathy underlies small vessel disease of the brain in a mouse model of Alzheimer's Disease

Mounting clinical and basic evidence has suggested that cerebral microcirculatory dysfunction is key to the pathogenesis of Alzheimer’s disease (AD), thus posing a potential new therapeutic target for AD treatment. However, despite observations of altered cerebral blood flow and autoregulatory capacity in AD patients, the underlying pathogenic mechanisms behind these defects are currently unknown. Here we present the first detailed study in to vascular ion channel function in the APP23 mouse model of AD. This model has a seven‐fold increase in amyloid precursor protein leading to substantial amyloid‐β plaque accumulation within the brain, as is described in AD patients. Using a range of physiological techniques; mainly pressure myography, patch clamp electrophysiology and high‐speed spinning disc confocal microscopy, we show that attenuation of large conductance calcium–activated potassium (BK) channel function in this model, due to a reduced frequency of calcium sparks, is responsible for the reduction in cerebral blood flow described. Further investigation into the role of amyloid‐β 1‐40, in particular, showed that vessels exposed to the peptide for 30 minutes exhibited significantly reduced BK channel function at both the cellular and vascular level. However, disparate from the APP23 mouse model, acute exposure to amyloid‐β 1‐40 resulted in an increase in calcium waves. Both a decrease in calcium sparks (as seen in the APP23 model) and an increase in calcium waves (as seen with acute application of the amyloid‐β 1‐40 peptide) results in contraction of cerebral arteries and a subsequent reduction of cerebral blood flow. The data directs future research in to preventative strategies that may help to stop alterations in calcium event initiation, restore microvasculature function and promote a healthy brain environment to limit disease progression in AD patients.

Embelin prevents amyloid-beta accumulation via modulation of SOD1 in a Streptozotocin-induced AD-like condition: An evidence from in vitro investigation.

Embelin is a neuroprotective compound with therapeutic benefit against experimental Alzheimer's disease (AD)-like condition. In the quest of untangling the underlying mechanism behind the neuroprotective effect of Embelin in AD, an in-vitro study of Embelin against neuronal damage induced by Streptozotocin (STZ) in rat hippocampal neuronal culture was performed. Current findings demonstrated that Embelin (2.5-10μM) has efficiently protected hippocampal neurons against STZ (8mM)-induced neurotoxicity. An increase in amyloid precursor protein (APP), microtubule-associated protein tau (MAPT), glycogen synthase kinase 3 alpha (GSK-3α) and glycogen synthase kinase 3 beta (GSK-3β) expression levels was observed when STZ (8mM) stimulation was done for 24h in the hippocampal neurons. A significant downregulation in the mRNA expression levels of APP, MAPT, GSK-3α, and GSK-3β upon pre-treatment with different doses of Embelin (2.5μM, 5μM and 10μM) reflects that Embelin attenuated STZ-induced dysfunction of insulin signaling (IR). Embelin significantly modulated the mRNA expression of scavenger enzyme Superoxide dismutase (SOD1). Furthermore, STZ had significantly upregulates an expression of Aβ. On the contrary, pre-treatment with three doses of Embelin reversed an Aβ-induced neuronal death. Our findings suggest that, Embelin prevents Aβ accumulation via SOD1 pathway to protect against AD-like condition.

Apolipoprotein E loss of function: Influence on murine brain markers of physiology and pathology.

The canonical role of Apolipoprotein E (ApoE) is related to lipid and cholesterol metabolism, however, additional functions of this protein have not been fully described. Given the association of ApoE with diseases such as Alzheimer's Disease (AD), it is clear that further characterisation of its roles, especially within the brain, is needed. Therefore, using protein and gene expression analyses of neonatal and 6-month old brain tissues from an ApoE knockout mouse model, we examined ApoE's contribution to several CNS pathways, with an emphasis on those linked to AD. Early neonatal changes associated with ApoE-/- were observed, with decreased soluble phosphorylated tau (p-tau, -40 %), increased synaptophysin (+36 %) and microglial Iba1 protein levels (+25 %) vs controls. Progression of the phenotype was evident upon analysis of 6-month-old tissue, where decreased p-tau was also confirmed in the insoluble fraction, alongside reduced synaptic and increased amyloid precursor protein (APP) protein levels. An age comparison further underlined deviations from WT animals and thus the impact of ApoE loss on neuronal maturation. Taken together, our data implicate ApoE modulation of multiple CNS roles. Loss of function is associated with alterations from birth, and include synaptic deficits, neuroinflammation, and changes to key AD pathologies, amyloid-β and tau.

APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation.

SummaryThe ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer’s disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol.

Pathological methamphetamine exposure triggers the accumulation of neuropathic protein amyloid-β by inhibiting UCHL1

Methamphetamine (METH), a powerful psychoactive drug, causes damage to the nervous system and leads to degenerative changes similar to Alzheimer's disease (AD), however, the molecular mechanism between the toxicity of METH and AD-related symptoms remains poorly understood. In this study, we investigated the effect of METH exposure on the accumulation of amyloid-β by establishing the animal and cell models. The results showed that METH exposure increased amyloid precursor protein (APP) and β-secretase (BACE1), contributed to the accumulation of amyloid-β, and which was alleviated with the pretreatment of BACE1 inhibitor. In addition, METH exposure decreased ubiquitin carboxy-terminal hydrolases L1 (UCHL1) which was related to the degradation of BACE1, and therefore led to the up-regulation of BACE1. In summary, the study could provide a new insight into the molecular mechanisms of METH toxicity and new evidence for the link between METH abuse and AD.

Genotype Load Modulates Amyloid Burden and Anxiety-Like Patterns in Male 3xTg-AD Survivors despite Similar Neuro-Immunoendocrine, Synaptic and Cognitive Impairments.

The wide heterogeneity and complexity of Alzheimer’s disease (AD) patients’ clinical profiles and increased mortality highlight the relevance of personalized-based interventions and the need for end-of-life/survival predictors. At the translational level, studying genetic and age interactions in a context of different levels of expression of AD-genetic-load can help to understand this heterogeneity better. In the present report, a singular cohort of long-lived (19-month-old survivors) heterozygous and homozygous male 3xTg-AD mice were studied to determine whether their AD-genotype load can modulate the brain and peripheral pathological burden, behavioral phenotypes, and neuro-immunoendocrine status, compared to age-matched non-transgenic controls. The results indicated increased amyloid precursor protein (APP) levels in a genetic-load-dependent manner but convergent synaptophysin and choline acetyltransferase brain levels. Cognitive impairment and HPA-axis hyperactivation were salient traits in both 3xTg-AD survivor groups. In contrast, genetic load elicited different anxiety-like profiles, with hypoactive homozygous, while heterozygous resembled controls in some traits and risk assessment. Complex neuro-immunoendocrine crosstalk was also observed. Bodyweight loss and splenic, renal, and hepatic histopathological injury scores provided evidence of the systemic features of AD, despite similar peripheral organs’ oxidative stress. The present study provides an interesting translational scenario to study further genetic-load and age-dependent vulnerability/compensatory mechanisms in Alzheimer’s disease.

Blast-Mediated Traumatic Brain Injury Exacerbates Retinal Damage and Amyloidosis in the APPswePSENd19e Mouse Model of Alzheimer's Disease.

PurposeTraumatic brain injury (TBI) is a risk factor for developing chronic neurodegenerative conditions including Alzheimer's disease (AD). The purpose of this study was to examine chronic effects of blast TBI on retinal ganglion cells (RGC), optic nerve, and brain amyloid load in a mouse model of AD amyloidosis.MethodsTransgenic (TG) double-mutant APPswePSENd19e (APP/PS1) mice and nontransgenic (Non-TG) littermates were exposed to a single blast TBI (20 psi) at age 2 to 3 months. RGC cell structure and function was evaluated 2 months later (average age at endpoint = 4.5 months) using pattern electroretinogram (PERG), optical coherence tomography (OCT), and the chromatic pupil light reflex (cPLR), followed by histologic analysis of retina, optic nerve, and brain amyloid pathology.ResultsAPP/PS1 mice exposed to blast TBI (TG-Blast) had significantly lower PERG and cPLR responses 2 months after injury compared to preblast values and compared to sham groups of APP/PS1 (TG-Sham) and nontransgenic (Non-TG-Sham) mice as well as nontransgenic blast-exposed mice (Non-TG-Blast). The TG-Blast group also had significantly thinner RGC complex and more optic nerve damage compared to all groups. No amyloid-β (Aβ) deposits were detected in retinas of APP/PS1 mice; however, increased amyloid precursor protein (APP)/Aβ-immunoreactivity was seen in TG-Blast compared to TG-Sham mice, particularly near blood vessels. TG-Blast and TG-Sham groups exhibited high variability in pathology severity, with a strong, but not statistically significant, trend for greater cerebral cortical Aβ plaque load in the TG-Blast compared to TG-Sham group.ConclusionsWhen combined with a genetic susceptibility for developing amyloidosis of AD, blast TBI exposure leads to earlier RGC and optic nerve damage associated with modest but detectable increase in cerebral cortical Aβ pathology. These findings suggest that genetic risk factors for AD may increase the sensitivity of the retina to blast-mediated damage.

Chromosomal aberrations and micronuclei structures after dermal exposure to polycyclic aromatic hydrocarbon and ultraviolet radiation

Lead exposure has been evidenced as a risk factor for Alzheimer’s disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks. We found that developmental lead exposure increased amyloid-beta (Aβ) accumulation and amyloid plaque deposition in the cortex and hippocampus. Lead exposure increased amyloid precursor protein (APP) expression and activated the sterol regulatory element binding protein 2 (SREBP2)-beta secretase (BACE1) pathway. In addition, we found that lead exposure decreased cholesterol levels by upregulating the expression of liver X receptor-a (LXR-a) and ATP-binding cassette transporter protein family member A1 (ABCA1) and decreasing the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDL-R) in young rat brain tissues. Taken together, our data demonstrated that developmental lead exposure induced early manifestation of AD-like pathology and disturbed cholesterol metabolism in young rat brains.

Lead exposure induces Alzheimers’s disease (AD)-like pathology and disturbes cholesterol metabolism in the young rat brain

Lead exposure has been evidenced as a risk factor for Alzheimer’s disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks. We found that developmental lead exposure increased amyloid-beta (Aβ) accumulation and amyloid plaque deposition in the cortex and hippocampus. Lead exposure increased amyloid precursor protein (APP) expression and activated the sterol regulatory element binding protein 2 (SREBP2)-beta secretase (BACE1) pathway. In addition, we found that lead exposure decreased cholesterol levels by upregulating the expression of liver X receptor-a (LXR-a) and ATP-binding cassette transporter protein family member A1 (ABCA1) and decreasing the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDL-R) in young rat brain tissues. Taken together, our data demonstrated that developmental lead exposure induced early manifestation of AD-like pathology and disturbed cholesterol metabolism in young rat brains.

LRP/LR specific antibody IgG1-iS18 impedes neurodegeneration in Alzheimer's disease mice.

Alzheimer’s disease (AD) is a neurodegenerative disease caused by accumulation of amyloid beta (Aβ) plaque and neurofibrillary tangle formation. We have shown in vitro, that knock-down and blockade of the 37 kDa/67 kDa Laminin Receptor (LRP/LR) resulted in reduced Aβ induced cytotoxicity and Aβ accumulation. In order to test the effect of blocking LRP/LR on Aβ formation and AD associated symptoms, AD transgenic mice received the anti-LRP/LR specific antibody, IgG1-iS18 through intranasal administration. We show that this treatment resulted in an improvement in memory, and decreased Aβ plaque formation. Moreover, a significant decrease in Aβ42 protein expression with a concomitant increase in amyloid precursor protein (APP) and telomerase reverse transcriptase (mTERT) levels was observed. These data recommend IgG1-iS18 as a potentially powerful therapeutic antibody for AD treatment.

Protective effects of curcumin on acrolein-induced neurotoxicity in HT22 mouse hippocampal cells.

Aging is one of the most important inevitable risk factors of Alzheimer disease (AD). Oxidative stress plays a critical role in the process of aging. Curcumin has been proposed to improve neural damage, especially neurodegenerative injury, through its antioxidant and anti-inflammatory properties. Therefore, we investigated the effects of curcumin on acrolein-induced AD-like pathologies in HT22 cells. HT22 murine hippocampal neuronal cells were treated with 25μM acrolein for 24h with or without pre-treating with curcumin at the selected optimum concentration (5μg/mL) for 30min. Cell viability and apoptosis were measured by CCK8 assay and flow cytometric analysis. Levels of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) were detected by a GSH assay kit or commercial assay kits, respectively. Alterations in the expression of BDNF/TrkB and key enzymes involved in amyloid precursor protein (APP) metabolism were assessed by western blotting. Data showed that curcumin significantly reversed acrolein-induced oxidative stress indicated by depletion of GSH and SOD, and elevation of MDA. The findings also suggested curcumin's potential in protecting HT22 cells against acrolein through regulating the BDNF/TrkB signaling. In addition, acrolein-induced reduction in A-disintegrin and metalloprotease, and the increase of amyloid precursor protein, β-secretase, and receptor for advanced glycation end products were reversed either, and most of them were nearly restored to the control levels by curcumin. These findings demonstrate the protective effects of curcumin on acrolein-induced neurotoxicity in vitro, which further suggests its potential role in the treatment of AD.

Inhibition of endothelial nitric oxide synthase reverses the effect of exercise on improving cognitive function in hypertensive rats.

Hypertension-induced endothelial dysfunction is associated with β-amyloid (Aβ) deposition, a typical pathology of Alzheimer's disease (AD). Endothelial nitric oxide synthase (eNOS) phosphorylation, impaired by phosphatidylinositol 3-kinase (PI3K)/protein kinase-B(Akt) pathway abnormalities in hypertensive rats, has a critical role in endothelial function. However, it is unknown whether eNOS participates in the hypertension-induced pathology of AD. In this study, we investigated the role of eNOS in Aβ deposition and cognitive function in stroke-prone spontaneously hypertensive (SHRSP) rats. Physical exercise was used as a promoter, and Nω-nitro L-arginine methyl ester (L-NAME) was used as an inhibitor of eNOS to determine the effects of eNOS on SHRSP rats. Compared with Wistar Kyoto (WKY) rats, the hypertensive challenge caused cognitive impairment, decreased eNOS levels and increased amyloid precursor protein (APP), β-secretase, and Aβ levels in the cortex and hippocampus. Sixteen weeks of exercise lowered blood pressure (BP), promoted eNOS expression, ameliorated Alzheimer's pathology, and improved cognitive function in 29-week-old SHRSP rats. Furthermore, daily treatment with L-NAME reversed the beneficial effects of exercise on SHRSP rats. Exercise also decreased the protein levels of insulin-like growth factor-1 (IGF-1), PI3K, and phospho-Akt (p-Akt, ser473). In addition, long-term exercise increased the expression levels of IGF-1, PI3K, and p-Akt (ser473) in the brains of SHRSP rats. In conclusion, eNOS downregulation contributed to hypertension-induced Alzheimer pathology and cognitive impairment. Long-term exercise initiated in rats at a young age promoted eNOS expression and attenuated vascular-related Alzheimer's pathology via the IGF-1/PI3K/p-Akt pathway in SHRSP rats.