Pathological Mechanism Of Alzheimer's Disease Research Articles

Development of amyloid beta-directed antibodies against Alzheimer's disease: Twists and turns.

Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease, and the treatment options that are currently available are limited. The amyloid cascade hypothesis has had a significant influence in explaining the pathology underlying AD. Inhibiting the production and aggregation of amyloid-beta (Aβ) and promoting its clearance have been important strategies in the development of anti-AD drugs over the past two decades. Specifically, Aβ directed antibodies have been highly anticipated, but drug development has been fraught with obstacles and challenges. Antibodies targeting the C-terminal or central region of Aβ, such as ponezumab, solanezumab, and crenezumab, primarily bind to Aβ monomers, yet no significant clearance of brain plaques or slowing of disease progression has been observed in clinical trials. Antibodies targeting the N-terminal region of Aβ, including aducanumab, lecanemab, and donanemab, primarily bind to aggregated forms of Aβ, and have shown efficacy in clearing brain plaques and slowing early-stage AD progression in clinical trials. However, clinical trials of gantenerumab, which targets conformational epitopes in the N-terminal and central sequences of Aβ and which selectively binds to aggregated forms, have failed, raising some new questions about the Aβ hypothesis. Advances in research on the pathological mechanisms of AD and advances in early diagnostic techniques may shift the time window for drug intervention and offer a potential pathway for developing effective drugs to delay the onset and progression of AD in the future.

A Study on Autophagy Related Biomarkers in Alzheimer's Disease Based on Bioinformatics.

Alzheimer's disease (AD) is a neurodegenerative disease with an annual incidence increase that poses significant health risks to people. However, the pathogenesis of AD is still unclear. Autophagy, as an intracellular mechanism can degrade damaged cellular components and abnormal proteins, which is closely related to AD pathology. The goal of this work is to uncover the intimate association between autophagy and AD, and to mine potential autophagy-related AD biomarkers by identifying key differentially expressed autophagy genes (DEAGs) and exploring the potential functions of these genes. GSE63061 and GSE140831 gene expression profiles of AD were downloaded from the Gene Expression Omnibus (GEO) database. R language was used to standardize and differentially expressed genes (DEGs) of AD expression profiles. A total of 259 autophagy-related genes were discovered through the autophagy gene databases ATD and HADb. The differential genes of AD and autophagy genes were integrated and analyzed to screen out DEAGs. Then the potential biological functions of DEAGs were predicted, and Cytoscape software was used to detect the key DEAGs. There were ten DEAGs associated with the AD development, including nine up-regulated genes (CAPNS1, GAPDH, IKBKB, LAMP1, LAMP2, MAPK1, PRKCD, RAB24, RAF1) and one down-regulated gene (CASP1). The correlation analysis reveals the potential correlation among 10 core DEAGs. Finally, the significance of the detected DEAGs expression was verified, and the value of DEAGs in AD pathology was detected by the receiver operating characteristic curve. The area under the curve values indicated that ten DEAGs are potentially valuable for the study of the pathological mechanism and may become biomarkers of AD. This pathway analysis and DEAG screening in this study found a strong association between autophagy-related genes and AD, providing new insights into the pathological progression of AD. Exploring the relationship between autophagy and AD: analysis of genes associated with autophagy in pathological mechanisms of AD using bioinformatics. 10 autophagy-related genes play an important role in the pathological mechanisms of AD.

Effectiveness and Safety of Bu Shen Kai Qiao Fang in the Treatment of Alzheimer's Disease: Study Protocol for a Multicenter, Prospective, Real-World Clinical Trial.

Alzheimer's disease (AD) is a common degenerative disease of the nervous system with serious impact on quality of life of patients and their families. With an aging population, AD has become a major public health problem in China and worldwide. However, the physiological and pathological mechanisms of AD have not been fully elucidated, and there is a lack of effective prevention and clinical treatment methods. Many studies have found that traditional Chinese medicine (TCM) has a good therapeutic effect on cognitive function in AD patients. Bu Shen Kai Qiao Fang (BSKQF) is one such Chinese herbal preparation used in the treatment of AD. We designed a protocol for a real-world clinical study of BSKQF combined with Donepezil hydrochloride (DH) to evaluate the efficacy and safety of this approach in the treatment of AD patients. This is a protocol for a real-world, multicenter, prospective, observational cohort study. The study will recruit 860 AD patients from four hospitals across China. Equal numbers of patients will be treated with BSKQF and DH or with DH only. The criteria for grouping are based primarily on patient preference. Outcome measures include scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MOCA) and will be recorded at baseline, and at one, two and three months after enrollment. The plasma Aβ42 and plasma Tau levels of participating patients will also be measured by ELISA at baseline and after 3 months of treatment. Safety metrics and adverse events (AEs) of participating patients will be monitored and recorded. This study will evaluate the clinical efficacy and safety of BSKQF in the treatment of AD. The results will provide reliable evidence for the clinical application of BSKQF in the treatment of AD. Trial registration: Chinese Clinical Trial Registry, NO. ChiCTR2000039670, Registered 5 November 2020 https://www.chictr.org.cn/showprojEN.html?proj=63800.

Activation of TRPV4 induces intraneuronal tau hyperphosphorylation via cholesterol accumulation

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel, whose aberrant function in neurons has been reported to participate in the progression of brain disorders, including Alzheimer's disease (AD). However, the influence of TRPV4 activation on tau hyperphosphorylation in AD has not yet been elucidated. Since disturbed brain cholesterol homeostasis is considered to be related to excessive tau phosphorylation, this study aimed to explore whether dysregulation of TRPV4 affects tau phosphorylation and whether it involves cholesterol unbalance. Our data indicated that TRPV4 activation increased tau phosphorylation in the cortex and hippocampus of P301S tauopathy mouse model and aggravated its cognitive decline. In addition, we detected that TRPV4 activation upregulated cholesterol levels in primary neurons, and the elevation of cholesterol promoted hyperphosphorylation of tau. TRPV4 knockdown improved tau hyperphosphorylation by reducing intracellular cholesterol accumulation. Our results suggest that activation of TRPV4 may take part in the pathological mechanism of AD by promoting intraneuronal tau hyperphosphorylation in a cholesterol-dependent manner.

Effect of sodium channels in Alzheimer’s disease

Alzheimer disease (AD), depicted by the formation of amyloid β-protein plaque(Aβ), has been recognized for dementia and epilepsy. The pathological mechanism of AD is complicated and it remains unclear. Currently, most therapies are focusing on elimination of Aβ plaque and preventing the breakdown of acetylcholine to prevent neuron cell death, however, most of these drugs fail to improve cognitive functions in AD patients. Therefore, the development of novel therapies for AD is in urgent need. Emerging evidences show that cellular sodium (Na+) signals play a significant role in neurol physiology. Aβ oligomer upregulates the expression of Nav1.6, leading to cognition loss, epilepsy, and malfunction of neuron development (shorter neurite length is observed during Aβ-interfered neuron development), indicating that sodium channel may be a target for treating AD. This review summarizes current development of molecular mechanisms linking sodium dysregulation with AD pathologies and discusses potential therapies for AD by correcting Na+ disruption.

Midazolam alleviates cellular senescence in SH-SY5Y neuronal cells in Alzheimer's disease.

Alzheimer's disease (AD) impacts the daily life of aging people. Oligomerized amyloid β (Aβ)-associated neuronal senescence is involved in the pathological mechanism of AD. Blockage of neuronal senescence has been considered an important strategy for the treatment of AD. Midazolam is a hypnotic-sedative drug with pleiotropic properties. However, the effects of Midazolam in oligomerized Aβ1.42 -induced neurotoxicity have not been reported previously. Here, we investigate whether Midazolam possesses a beneficial effect against oligomerized Aβ1.42 in SH-SY5Y neuronal cells. Cellular senescence was assessed using senescence-associated β-galactosidase staining. Telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISA. First, the lactate dehydrogenase release assay demonstrates that 10 and 20 µM are the optimal concentrations of Midazolam used for cell cultures. Senescence-associated β-galactosidase staining results indicate that exposure to oligomerized Aβ1.42 significantly increased cellular senescence of SH-SY5Y cells, but it was significantly alleviated by Midazolam. Additionally, Midazolam restored the oligomerized Aβ1.42 -induced reduction of telomerase activity. Interestingly, we found that oligomerized Aβ1.42 remarkably reduced human telomerase reverse transcriptase (hTERT) gene expression but increased the telomeric repeat-binding factor 2 (TERF2) expression. However, treatment with Midazolam reversed the effects of oligomerized Aβ1.42 on the hTERT and TERF2 gene expressions. Importantly, the presence of Midazolam attenuated Aβ1.42 -induced p53 and p21 expressions. Mechanistically, Midazolam repressed the level of cyclooxygenase-2 (COX-2) and the release of prostaglandin E2. Importantly, overexpression of COX-2 abolished the impact of Midazolam against oligomerized Aβ1.42 in neuronal senescence. We conclude that the usage of Midazolam is a potential treatment strategy for AD.

White matter integrity disruption in the pre-dementia stages of Alzheimer's disease: from subjective memory impairment to amnestic mild cognitive impairment.

Subjective memory impairment (SMI) and amnestic mild cognitive impairment (aMCI) are thought to represent the pre-dementia stages of Alzheimer's disease (AD). SMI is considered a more advanced pre-clinical status prior to aMCI. Understanding the neuromechanism of SMI will have great benefits for monitoring the disease progression of AD. The study aims to explore whether SMI shows alterations of white matter (WM) integrity similar to the patterns of aMCI. The atlas-based analyses were performed to investigate the diffusion changes in the major WM tracts amongst 22 individuals with normal cognition (NC), 22 SMI patients and 25 aMCI patients. The correlations between the altered diffusion metrics and cognitive performance in the SMI and aMCI groups were assessed. The diffusion tensor metrics of SMI were intermediate between the NC and aMCI groups. The aMCI group presented disrupted integrity in multiple WM tracts, including the left anterior thalamic radiation, right corticospinal tract and left cingulum of the hippocampus (CgH), compared to the NC group. The left CgH showed diffusion alterations in the SMI group. In the aMCI group, the mean diffusivity of the left CgH was negatively correlated with episodic memory, whilst the radial diffusivity of the right corticospinal tract was negatively correlated with executive function. No significant relationship was found in the SMI group. The study suggested that SMI patients might present detectable WM integrity changes in the left CgH before exhibiting objective cognitive dysfunction, which may provide novel insights into the pathological mechanisms of AD.

Abnormal organization of white matter networks in patients with subjective cognitive decline and mild cognitive impairment

Network analysis has been widely used in studying Alzheimer's disease (AD). However, how the white matter network changes in cognitive impaired patients with subjective cognitive decline (SCD) (a symptom emerging during early stage of AD) and amnestic mild cognitive impairment (aMCI) (a pre-dementia stage of AD) is still unclear. Here, structural networks were constructed respectively based on FA and FN for 36 normal controls, 21 SCD patients, and 33 aMCI patients by diffusion tensor imaging and graph theory. Significantly lower efficiency was found in aMCI patients than normal controls (NC). Though not significant, the values in those with SCD were intermediate between aMCI and NC. In addition, our results showed significantly altered betweenness centrality located in right precuneus, calcarine, putamen, and left anterior cingulate in aMCI patients. Furthermore, association was found between network metrics and cognitive impairment. Our study suggests that the structural network properties might be preserved in SCD stage and disrupted in aMCI stage, which may provide novel insights into pathological mechanisms of AD.

The Rationale for Insulin Therapy in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD.

The Role of Cdk5 in Alzheimer's Disease.

Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

Small-worldness of functional networks in Alzheimer's disease

To construct the functional networks of human brains by resting-state functional magnetic resonance imaging (fMRI) and examine whether or not the small-world property of functional brain networks changes in patients with Alzheimer disease (AD). A total of 33 AD patients and 20 healthy old volunteers were recruited. Their cognitive functions were evaluated by the mini-mental state examination (MMSE) and Mattis dementia rating scale (DRS). The resting-state BOLD-fMRI data were acquired and preprocessed. Then the correlation coefficient of every pair of 90 regions was calculated and correlation matrix Z (N×N, N = 90) generated by Fisher Z transformation. The small-world property of functional brain networks was tested for AD patients and normal elders according to the definition of small-worldness. The changes of relevant parameters in AD patients were examined by two sample t-tests. Behavioral results: the MMSE scores of AD group and normal controls (NOR) were 20.60 ± 2.30 and 28.20 ± 1.80 respectively. The DRS scores of AD and NOR groups were 96.00 ± 10.82 and 123.22 ± 13.74 respectively. The MMSE and DRS scores were statistically different between two groups. Calculation of small-world parameters: Within the range of 0.1 ≤ Sparsity ≤ 0.4, both groups satisfied the small-world property. However, the clustering coefficient Cp and the average shortest path Lp of AD group were significantly higher than those of NOR group at each threshold (P < 0.05). The functional brain networks in AD patients still have the property of small-world. But the levels of Cp and Lp are higher in AD patients than those in normal controls. It suggests that the capacity of information transmission in functional brain networks and the ability of information integration in different brain regions in AD patients are impaired. This finding is of great importance in elucidating the pathological mechanisms of AD from the viewpoint of networks.

Relationship between atrophy and β‐amyloid deposition in Alzheimer disease

AbstractObjectiveElucidating the role of aggregated β‐amyloid in relation to gray matter atrophy is crucial to the understanding of the pathological mechanisms of Alzheimer disease and for the development of therapeutic trials. The present study aims to assess this relationship.MethodsBrain magnetic resonance imaging and [11C]Pittsburgh compound B (PiB)‐positron emission tomography scans were obtained from 94 healthy elderly subjects (49 with subjective cognitive impairment), 34 patients with mild cognitive impairment, and 35 patients with Alzheimer disease. The correlations between global and regional neocortical PiB retention and atrophy were analyzed in each clinical group.ResultsGlobal and regional atrophy were strongly related to β‐amyloid load in participants with subjective cognitive impairment but not in patients with mild cognitive impairment or Alzheimer disease. Global neocortical β‐amyloid deposition correlated to atrophy in a large brain network including the hippocampus, medial frontal and parietal areas, and lateral temporoparietal cortex, whereas regional β‐amyloid load was related to local atrophy in the areas of highest β‐amyloid load only, that is, medial orbitofrontal and anterior and posterior cingulate/precuneus areas.InterpretationThere is a strong relationship between β‐amyloid deposition and atrophy very early in the disease process. As the disease progresses to mild cognitive impairment and Alzheimer disease clinical stages, pathological events other than, and probably downstream from, aggregated β‐amyloid deposition might be responsible for the ongoing atrophic process. These findings suggest that antiamyloid therapy should be administered very early in the disease evolution to minimize synaptic and neuronal loss. ANN NEUROL 2010;67:317–324

L-Theanine, an amino acid in green tea, attenuates β-amyloid-induced cognitive dysfunction and neurotoxicity: Reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-κB pathways

Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer disease (AD). In this study, we investigated the inhibitory effect of l-theanine, a component of green tea ( Camellia sinensis), on Aβ 1-42-induced neuronal cell death and memory impairment. Oral treatment of l-theanine (2 and 4 mg/kg) for 5 weeks in the drinking water of mice, followed by injection of Aβ 1-42 (2 μg/mouse, icv), significantly attenuated Aβ 1-42-induced memory impairment. Furthermore, l-theanine reduced Aβ 1-42 levels and the accompanying Aβ 1-42-induced neuronal cell death in the cortex and hippocampus of the brain. Moreover, l-theanine inhibited Aβ 1-42-induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase as well as the activity of nuclear factor κB (NF-κB). l-Theanine also significantly reduced oxidative protein and lipid damage and the elevation of glutathione levels in the brain. These data suggest that the positive effects of l-theanine on memory may be mediated by suppression of ERK/p38 and NF-κB as well as the reduction of macromolecular oxidative damage. Thus, l-theanine may be useful in the prevention and treatment of AD.