Cause Of Alzheimer's Disease Research Articles

The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence.

Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβantibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval. HIGHLIGHTS: Thirteen key findings support amyloid beta as a cause of Alzheimer's disease (AD). Three immunotherapies lower amyloid and slow decline, allowing regulatory approval. New such agents could be considered for approval due to amyloid lowering and safety. Urgency suggests AD may join diseases with approval due to a key biomarker + safety.

Exploring bacterial metabolites in microbe-human host dialogue and their therapeutic potential in Alzheimer's diseases.

Neurological dysfunction in association with aging, dementia, and cognitive impairment is the major cause of Alzheimer's disease (AD). Current AD therapies often yield unsatisfactory results due to their poor mechanism in treating the underlying mechanism of the disease. Recent studies suggested that metabolites from the gut microbiota facilitate brain-gut communication. A systematic network pharmacology study and the structure- and analog-based approaches are employed to investigate the metabolites produced by gut microbiota to treat AD. The microbiota metabolites available in the gutMGene database were considered in this study. Two servers, namely Swiss Target Prediction (STP) and Similarity Ensemble Approach (SEA), were used to identify the possible AD targets for the selected metabolites. Detailed KEGG pathway and Gene Ontology (GO) analysis on identified hub genes highlighted the importance of IL6, AKT1, and GSK3B in AD pathophysiology. MMTSp (Microbiota Metabolites Target Signaling pathways) network analysis elucidated that there is a strong relationship with microbiota (Paraprevotella xylaniphila YIT 11841, Bifidobacterium dentium, Paraprevotella clara YIT 11840, Enterococcus sp. 45, Bacteroides sp. 45, Bacillus sp. 46, Escherichia sp. 33, Enterococcus casseliflavus, Bacteroides uniformis, Alistipes indistinctus YIT 12060, Bacteroides ovatus, Escherichia sp. 12, and Odoribacter laneus YIT 12061) and AD pathogenesis. In addition to this, we performed molecular docking to study the metabolite interactions in the AD drug targets. The ADME/T properties of these metabolites were also calculated and the results are discussed in detail.

A promising drug repurposing approach for Alzheimer's treatment: Givinostat improves cognitive behavior and pathological features in APP/PS1 mice.

Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by memory loss, speech and motor defects, personality changes, and psychological disorders. The exact cause of AD remains unclear. Current treatments focus on maintaining neurotransmitter levels or targeting β-amyloid (Aβ) protein, but these only alleviate symptoms and do not reverse the disease. Developing new drugs is time-consuming, costly, and has a high failure rate. Utilizing multi-omics for drug repositioning has emerged as a new strategy. Based on transcriptomic perturbation data of over 40,000 drugs in human cells from the LINCS-L1000 database, our study employed the Jaccard index and hypergeometric distribution test for reverse transcriptional feature matching analysis, identifying Givinostat as a potential treatment for AD. Our research found that Givinostat improved cognitive behavior and brain pathology in models and enhanced hippocampal synaptic plasticity. Transcriptome sequencing revealed increased expression of mitochondrial respiratory chain complex proteins in the brains of APP/PS1 mice after Givinostat treatment. Functionally, Givinostat restored mitochondrial membrane potential, reduced reactive oxygen species, and increased ATP content in Aβ-induced HT22 cells. Additionally, it improved mitochondrial morphology and quantity in the hippocampus of APP/PS1 mice and enhanced brain glucose metabolic activity. These effects are linked to Givinostat promoting mitochondrial biogenesis and improving mitochondrial function. In summary, Givinostat offers a promising new strategy for AD treatment by targeting mitochondrial dysfunction.

The discovery of JAL-TA9 which cleaves amyloid-β with proteolytic activity

Amyloid-β (Aβ) 42, one of the causes of Alzheimer's disease (AD), is produced by the cleavage of amyloid precursor protein (APP) by β- or γ-secretases. Since Aβ42 oligomers exhibit strong neurotoxicity, Aβ42 is predicted to be a potentially efficient target for drug therapies. Recently, we screened peptides that activate MMP7 using our peptide library and found that the synthetic peptide JAL-TA9 (YKGSGFRMI), which is derived from the BoxA region of Tob1 protein, showed proteolytic activity. It is generally accepted that an enzyme should be a large molecular protein consisting of more than thousands of amino acids. Thus, this is the first finding that a small synthetic peptide has protease activity, and we termed Catalytide as the general name of peptides with protease activity. In this study, we demonstrate the cleavage activity of JAL-TA9 not only against the authentic soluble form of Aβ42 but also against the solid type of Aβ42 in the central region. In addition, we demonstrated the cleavage activity using brain slices of AD patients. JAL-TA9 decreased the amount of accumulated Aβ42 in the brain of Alzheimer's patients. Taken together, JAL-TA9 is an attractive seed for the development of peptide drugs with a new strategy for Alzheimer's disease.

Anti-inflammatory response controlled by gamma wave

It is now believed that the cause of Alzheimer’s disease is the accumulation of amyloid-Bata, which is caused by a variety of factors, such as neuroinflammation. So in this study, the researchers will study the changes of microglia from M1 to M2 by changing the frequency of gamma wave. If microglia change from M1 to M2, that means it changes from pro-inflammatory to anti-inflammatory.

The Role of Non-Coding RNAs in Mitochondrial Dysfunction of Alzheimer's Disease.

Although brain amyloid-β (Aβ) peptide buildup is the main cause of Alzheimer's disease (AD), mitochondrial abnormalities can also contribute to the illness's development, as either a primary or secondary factor, as programmed cell death and efficient energy generation depend on the proper operation of mitochondria. As a result, non-coding RNAs (ncRNAs) may play a crucial role in ensuring that nuclear genes related to mitochondria and mitochondrial genes function normally. Interestingly, a significant number of recent studies have focused on the impact of ncRNAs on the expression of nucleus and mitochondrial genes. Additionally, researchers have proposed some intriguing therapeutic approaches to treat and reduce the severity of AD by adjusting the levels of these ncRNAs. The goal of this work was to consolidate the existing knowledge in this field of study by systematically investigating ncRNAs, with a particular emphasis on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs). Therefore, the impact and processes by which ncRNAs govern mitochondrial activity in the onset and progression of AD are thoroughly reviewed in this article. Collectively, the effects of ncRNAs on physiological and molecular mechanisms associated with mitochondrial abnormalities that exacerbate AD are thoroughly reviewed in the current research, while also emphasizing the relationship between disturbed mitophagy in AD and ncRNAs.

Impaired glymphatic clearance is an important cause of Alzheimer’s disease

Impaired glymphatic clearance is an important cause of Alzheimer’s disease

Licochalcone A Ameliorates Cognitive Dysfunction in an Alzheimer's Disease Model by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis.

Endoplasmic reticulum (ER) stress-induced neurodegeneration has been considered an underlying cause of Alzheimer disease (AD). Here, we investigated the beneficial effects of licochalcone A (Lico A), a valuable flavonoid of the root of the Glycyrrhiza species, against cognitive impairment in AD by regulating ER stress. The triple transgenic mouse AD models were used and were administrated 5 or 15mg/kg Lico A. Cognitive deficits, Aβ deposition, ER stress, and neuronal apoptosis were determined using Morris Water Maze test, probe trial, immunofluorescence staining, western blotting, and TUNEL staining. To investigate the mechanisms of how Lico A exerts anti-AD effects, primary hippocampal neurons were isolated from the AD model mice and treated with Lico A, salubrinal, an eIF2α phosphatase inhibitor, ML385, a Nrf2 inhibitor, or LY294002, an inhibitor of PI3K. Pharmacokinetics and toxicity of Lico A (15mg/kg) in AD mice were evaluated. We found that Lico A improved cognitive impairment, decreased Aβ plaques, inhibited ER stress, and reduced neuronal apoptosis in the hippocampus and cortex of AD mice. Treatment with Lico A in primary hippocampal neurons exerted the same effects as it did in vivo. Additionally, cotreatment with ML385 or LY294002 significantly impeded the effects of Lico A against ER stress. Moreover, 15mg/kg Lico A had a good bioavailability and low toxicity in AD mice. Our results demonstrated that Lico A ameliorates ER stress-induced neuronal apoptosis by inhibiting PERK/eIF2α/ATF4/CHOP signaling, suggesting the therapeutic potential of Lico A in AD treatment.

Nasal lymphatic obstruction of CSF drainage as a possible cause of Alzheimer's disease and dementia.

Alzheimer's disease, the most common form of dementia among older adults, slowly destroys memory and thinking skills. In recent years, scientists have made tremendous progress in understanding Alzheimer's disease, still, they do not yet fully understand what causes the disease. This article proposes a novel etiology for Alzheimer's disease. Our hypothesis developed from a review of nuclear medicine scans, in which the authors observed a significant increase in nasal turbinate vasodilation and blood pooling in patients with hypertension, sleep apnea, diabetes and/or obesity, all risk factors for Alzheimer's disease. The authors propose that nasal turbinate vasodilation and resultant blood pooling lead to the obstruction of normal nasal lymphatic clearance of cerebrospinal fluid and its waste products from the brain. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs alongside the well-established increased sympathetic activity of the cardiovascular system as seen in patients with hypertension. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of highly processed food associated with dysregulation of the glucose regulatory system. The authors' hypothesis offers a novel mechanism and a new paradigm for the etiology of Alzheimer's disease and helps explain the rapid worldwide rise in the disease and other dementias which are expected to double in the next 20 years. This new paradigm provides compelling evidence for the modulation of the parasympathetic nervous system as a novel treatment strategy for Alzheimer's disease and other degenerative brain diseases, specifically targeting nasal turbinate lymphatic flow.

Application of CRISPR/Cas9 gene-editing technology in Alzheimers disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. It triggers metabolic disorders within the body due to genetic mutations, thus leading to irreversible damage to one's memory and brain. The primary pathogenic features of AD are intracellular neurofibrillary tangles caused by hyperphosphorylated Tau and extracellular amyloid plaques created by the buildup of -amyloid -protein (A). However, up to now, there has been no effective treatment program for Alzheimer's disease. And after a long time of development, many gene editing technologies have been perfected and utilized in practice. Among them, CRISPR-Cas9 technology is the most efficient and practical. As a result, an increasing number of scientists have examined and debated the potential use of CRISPR-Cas9 technology in the management of Alzheimer's disease. This review addresses the use of the CRISPR/Cas9 system to treat Alzheimer's disease and presents the disease's pathophysiology, including the establishment of AD models, genetic screening for the cause of AD, and targeted therapy for AD.

The gut microbiota as a link between Alzheimer's disease and obesity.

Alzheimer's disease (AD) is a degenerative disease that causes a progressive decline in memory and thinking skills. Over the past few years, diverse studies have shown that there is no single cause of AD; instead, it has been reported that factors such as genetics, lifestyle, and environment contribute to the pathogenesis of the disease. In this sense, it has been shown that obesity during middle age is one of the most prominent modifiable risk factors for AD. Of the multiple potential mechanisms linking obesity and AD, the gut microbiota (GM) has gained increasing attention in recent years. However, the underlying mechanisms that connect the GM with the process of neurodegeneration remain unclear. Through this narrative review, we present a comprehensive understanding of how alterations in the GM of people with obesity may result in systemic inflammation and affect pathways related to the pathogenesis of AD. We conclude with an analysis of the relationship between GM and insulin resistance, a risk factor for AD that is highly prevalent in people with obesity. Understanding the crosstalk between obesity, GM, and the pathogenesis of AD will help to design new strategies aimed at preventing neurodegeneration.

Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation.

Mutations in PSEN1 were first discovered as a cause of Alzheimer's disease (AD) in 1995, yet the mechanism(s) by which the mutations cause disease still remains unknown. The generation of novel mouse models assessing the effects of different mutations could aid in this endeavor. Here we report on transgenic mouse lines made with the Δ440 PSEN1 mutation that causes AD with parkinsonism:- two expressing the un-tagged human protein and two expressing a HA-tagged version. Detailed characterization of these lines showed that Line 305 in particular, which expresses the untagged protein, develops age-dependent memory deficits and pathologic features, many of which are consistent with features found in AD. Key behavioral and physiological alterations found in the novel 305 line included an age-dependent deficit in spontaneous alternations in the Y-maze, a decrease in exploration of the center of an open field box, a decrease in the latency to fall on a rotarod, a reduction in synaptic strength and pair-pulse facilitation by electrophysiology, and profound alterations to cerebral blood flow regulation. The pathologic alterations found in the line included, significant neuronal loss in the hippocampus and cortex, astrogliosis, and changes in several proteins involved in synaptic and mitochondrial function, Ca2+ regulation, and autophagy. Taken together, these findings suggest that the transgenic lines will be useful for the investigation of AD pathogenesis.

Investigation of amyloid‑β peptide production and clearance pathways in different stages of Alzheimer's disease.

Alzheimer's disease (AD) is an age‑related, progressive decline in cognitive ability. Accumulation and deposition of amyloid‑β (Aβ) is still the best‑known cause of AD that worsens over time. It is unclear whether the increase in Aβ production or the inefficiency of the degradation system causes the accumulation of β‑fibrils during AD development. This research investigated Aβ‑producing and clearance pathways in different stages of AD. For this purpose, patients were categorized into four experimental groups: patients with mild cognitive impairment, patients with moderate cognitive decline, patients with very severe cognitive decline, and healthy patients as control. Levels of Aβ‑40, soluble amyloid precursor protein beta (sAPPβ), matrix metalloproteinase‑9 (MMP‑9), matrix metalloproteinase‑3 (MMP‑3), neprilysin (NEP), angiotensin‑converting enzyme (ACE), and insulin‑degrading enzyme (IDE) were determined by ELISA kits and immunoblotting in serum samples. According to the results, the levels of Aβ‑40 and sAPPβ increased in AD patients from an early stage, and levels were maintained in progressive AD stages. MMP‑9 also increased in the early stage, but its content decreased with disease development. MMP‑3 was significantly higher in the three stages of AD compared to the control patients. However, IDE, NEP, and ACE enzymes as clearing systems decreased in all studied AD samples, with their reductions more remarkable in the middle and late stages. The results showed that multiple Aβ‑degrading enzymes such as NEP and IDE in AD patients decline as AD progresses, while Aβ‑40 and sAPPβ increased from the early stage of the disease. Therefore, it could be concluded that detection of the dementia phase is a critical step for therapeutic strategies.

A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aβ42 Fibrils Confirmed by In Vitro Studies.

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid β fibrils, which is extremely important for applications in Alzheimer's disease therapy.

Alzheimer’s disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis

ObjectiveMutations in presenilin genes are the major cause of Alzheimer’s disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins...

Alzheimer’s Disease: An Outline of Therapeutic Interventions by different Approaches

A neurodegenerative condition called Alzheimer's disease (AD) impairs neurocognitive function and hinders the growth of mental ability. This neuropathological condition presents with neurodegeneration, neuronal loss, and the development of neurofibrillary tangles and Ab plaques. Dementia, neuronal loss, and the development of neurofibrillary tangles and Ab plaques are the hallmarks of this neuropathological disorder. Such a medication is not able to cure Alzheimer's disease. The drug that's now available just treats symptoms. Two major obstacles to research are the blood-brain barrier, which reduces the effectiveness of treatments, and the incomplete comprehension of the ethology of Alzheimer's disease. Stem cell-based therapy has been seen as a novel, reliable and successful restoration technique to treat AD since the condition is complex and has not gotten much attention. The latest advances in nanotechnology occasionally offer proactive treatment chances that can help get over limitations. In this overview, we concentrate on the causes of AD and the various methods used to treat them.

Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids.

Mono- and polyunsaturated fatty acids (FAs) are broadly used as food supplements. However, their effect on the aggregation of amyloidogenic proteins remains unclear. In this study, we investigated the effect of a large number of mono- and polyunsaturated, as well as fully saturated FAs on the aggregation of amyloid β1-42 (Aβ1-42) peptide. A progressive aggregation of this peptide is the expected molecular cause of Alzheimer's disease (AD), one of the most common neurodegenerative pathologies in the world. We found that arachidonic and stearic acids delayed the aggregation of Aβ1-42. Using Nano-Infrared spectroscopy, we found that FAs caused very little if any changes in the secondary structure of Aβ1-42 oligomers and fibrils formed at different stages of protein aggregation. However, the analyzed mono- and polyunsaturated, as well as fully saturated FAs uniquely altered the toxicity of Aβ1-42 fibrils. We found a direct relationship between the degree of FAs unsaturation and toxicity of Aβ1-42 fibrils formed in their presence. Specifically, with an increase in the degree of unsaturation, the toxicity Aβ1-42/FA fibrils increased. These results indicate that fully saturated or monounsaturated FAs could be used to decrease the toxicity of amyloid aggregates and, consequently, decelerate the development of AD.

Beliefs About the Causes of Alzheimer's Disease Among Latinos in New York City.

Latinos face health disparities in Alzheimer's disease (AD), with high disease prevalence relative to non-Latino whites and barriers to healthcare access. Several studies have found misconceptions about AD among Latinos that were linked to reduced preventative or help-seeking behavior. To improve understanding of illness perceptions among Latinos, we examined beliefs about the causes of AD, one of the five dimensions of illness representations from Leventhal's Self-Regulation Theory, among a sample of N = 216 Latinos. We conducted in-depth, semi-structured interviews with participants aged 40 to 64 (average age 53 years) living in northern Manhattan. Seven distinct causes of AD were identified, though participants demonstrated a general understanding of AD as a multifactorial disease. Genetics was found to be the most endorsed cause of AD, followed by unhealthy lifestyle factors. Most Latinos who believed psychosocial factors played a critical role in AD development were first-generation immigrants. No participants attributed AD to a normal process of aging, and few ascribed the disease to brain damage from stroke or head injuries. Several participants expressed the belief that environmental contaminants can cause AD, which has received little mention in prior studies. Though only a small number thought AD could occur by chance, most participants remained uncertain about the exact causes of the disease and used lay knowledge to explain their beliefs. Our findings help identify areas where educational interventions would be beneficial in improving community knowledge and offer perspectives that can foster cultural competency in healthcare.

A Cationic Zn-Phthalocyanine Turns Alzheimer's Amyloid β Aggregates into Non-Toxic Oligomers and Inhibits Neurotoxicity in Culture.

Amyloid β peptide (Aβ) aggregation and deposition are considered the main causes of Alzheimer's disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aβ peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood-brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aβ1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aβ1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aβ1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aβ1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aβ1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer's disease.

The Association between Long Non-Coding RNAs and Alzheimer's Disease.

Neurodegeneration occurs naturally as humans age, but the presence of additional pathogenic mechanisms yields harmful and consequential effects on the brain. Alzheimer's disease (AD), the most common form of dementia, is a composite of such factors. Despite extensive research to identify the exact causes of AD, therapeutic approaches for treating the disease continue to be ineffective, indicating important gaps in our understanding of disease mechanisms. Long non-coding RNAs (lncRNAs) are an endogenous class of regulatory RNA transcripts longer than 200 nucleotides, involved in various regulatory networks, whose dysregulation is evident in several neural and extraneural diseases. LncRNAs are ubiquitously expressed across all tissues with a wide range of functions, including controlling cell differentiation and development, responding to environmental stimuli, and other physiological processes. Several lncRNAs have been identified as potential contributors in worsening neurodegeneration due to altered regulation during abnormal pathological conditions. Within neurological disease, lncRNAs are prime candidates for use as biomarkers and pharmacological targets. Gender-associated lncRNA expression is altered in a gender-dependent manner for AD, suggesting more research needs to be focused on this relationship. Overall, research on lncRNAs and their connection to neurodegenerative disease is growing exponentially, as commercial enterprises are already designing and employing RNA therapeutics. In this review we offer a comprehensive overview of the current state of knowledge on the role of lncRNAs in AD and discuss the potential implications of lncRNA as potential therapeutic targets and diagnostic biomarkers in patients with Alzheimer's disease.