A Look at the Etiology of Alzheimer's Disease based on the Brain Ischemia Model.

Alzheimer's disease (AD) is the frequent form of dementia in the world. Despite over 100 years of research into the causes of AD, including amyloid and tau protein, the research has stalled and has not led to any conclusions. Moreover, numerous projects aimed at finding a cure for AD have also failed to achieve a breakthrough. Thus, the failure of anti-amyloid and anti-tau protein therapy to treat AD significantly influenced the way we began to think about the etiology of the disease. This situation prompted a group of researchers to focus on ischemic brain episodes, which, like AD, mostly present alterations in the hippocampus. In this context, it has been proposed that cerebral ischemic incidents may play a major role in promoting amyloid and tau protein in neurodegeneration in AD. In this review, we summarized the experimental and clinical research conducted over several years on the role of ischemic brain episodes in the development of AD. Studies have shown changes typical of AD in the course of brain neurodegeneration post-ischemia, i.e., progressive brain and hippocampal atrophy, increased amyloid production, and modification of tau protein. In the post-ischemic brain, the diffuse and senile amyloid plaques and the development of neurofibrillary tangles characteristic of AD were revealed. The above data evidently showed that after brain ischemia, there are modifications in protein folding, leading to massive neuronal death and damage to the neuronal network, which triggers dementia with the AD phenotype.

Higher Cerebrospinal Fluid Levels of Amyloid-ß40 Following Traumatic Brain Injury Relate to Confrontation Naming Performance.

Background: Traumatic brain injury (TBI) may confer risk for Alzheimer's disease (AD) through amyloid-ß (Aß) overproduction. However, the relationship between TBI and Aß levels in cerebrospinal fluid (CSF) remains unclear. Objective: To explore whether Aß overproduction is implicated in the relationship between TBI and AD, we compared CSF levels of Aß in individuals with a TBI history versus controls (CTRLs) and related CSF Aß levels to cognitive markers associated with preclinical AD. Methods: Participants were 112 non-impaired Veterans (TBI = 56, CTRL = 56) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense database with available cognitive data (Boston Naming Test [BNT], Rey Auditory Verbal Learning Test [AVLT]) and CSF measures of Aß42, Aß40, and Aß38. Mediation models explored relationships between TBI history and BNT scores with Aß peptides as mediators. Results: The TBI group had higher CSF Aß40 (t = -2.43, p = 0.017) and Aß38 (t = -2.10, p = 0.038) levels than the CTRL group, but groups did not differ in CSF Aß42 levels or Aß42/Aß40 ratios (p > 0.05). Both Aß peptides negatively correlated with BNT (Aß40: rho = -0.20, p = 0.032; Aß38: rho = -0.19, p = 0.048) but not AVLT (p > 0.05). Aß40 had a significant indirect effect on the relationship between TBI and BNT performance (ß= -0.16, 95% CI [-0.393, -0.004], PM = 0.54). Conclusions: TBI may increase AD risk and cognitive vulnerability through Aß overproduction. Biomarker models incorporating multiple Aß peptides may help identify AD risk among those with TBI.

A Review of Recent Advances in the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aß) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aß plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer's Disease: A Narrative Review.

The escalating prevalence of Alzheimer's disease (AD) highlights the urgent need to develop reliable biomarkers for early diagnosis and intervention. AD is characterized by the pathological accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Phosphorylated tau (p-tau) proteins, particularly p-tau217 and p-tau231, have been identified as promising biomarker candidates to differentiate the disease progression from preclinical stages. This narrative review is devoted to a critical evaluation of the diagnostic accuracy, sensitivity, and specificity of p-tau217 and p-tau231 levels in the detection of AD, measured in plasma, serum, and cerebrospinal fluid, compared to established biomarkers. Additionally, the efficacy of these markers in distinguishing AD from other neurodegenerative disorders is examined. The significant advances offered by p-tau217 and p-tau231 in AD diagnostics are highlighted, demonstrating their unique utility in early detection and differential diagnosis. This comprehensive analysis not only confirms the excellent diagnostic capabilities of these markers, but also deepens the understanding of the molecular dynamics of AD, contributing to the broader scientific discourse on neurodegenerative diseases. This review is aimed to provide key information for researchers and clinicians across disciplines, filling interdisciplinary gaps and highlighting the role of p-tau proteins in revolutionizing AD research and clinical practice.

Peripheral HMGB1 is linked to O3 pathology of disease-associated astrocytes and amyloid.

INTRODUCTION: Ozone (O3) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung-brain axis is implicated in O3-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown. METHODS: The O3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1fl/fl LysM-Cre+ mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1). RESULTS: O3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O3-exposed Hmgb1fl/fl LysM-Cre+ mice exhibited dysregulated DAA mRNA markers. DISCUSSION: Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology. HIGHLIGHTS: Astrocytes are part of the lung-brain axis, regulating how air pollution affects plaque pathology. Ozone (O3) astrocyte effects are associated with increased plaques and modified by plaque localization. O3 uniquely disrupts the astrocyte transcriptomic and proteomic disease-associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O3 changes the PAA cell contact with microglia and cell-cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O3-induced transcriptomic changes in the DAA phenotype.

Microglia and amyloid plaque formation in Alzheimer's disease - Evidence, possible mechanisms, and future challenges.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that severely affects patients and their families. Genetic and environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. Genetic risk factors for late-onset AD (LOAD), which accounts for most AD cases, are predominantly implicated in microglial and immune cell functions. As such, microglia play a major role in formation of amyloid beta (Aß) plaques, the major pathological hallmark of AD. This review aims to provide an overview of the current knowledge regarding the role of microglia in Aß plaque formation, as well as their impact on morphological and functional diversity of Aß plaques. Based on this discussion, we seek to identify challenges and opportunities in this field with potential therapeutic implications.

Application of CRISPR/Cas9 System in the Treatment of Alzheimer's Disease and Neurodegenerative Diseases.

Alzheimer's, Parkinson's, and Huntington's are some of the most common neurological disorders, which affect millions of people worldwide. Although there have been many treatments for these diseases, there are still no effective treatments to treat or completely stop these disorders. Perhaps the lack of proper treatment for these diseases can be related to various reasons, but the poor results related to recent clinical research also prompted doctors to look for new treatment approaches. In this regard, various researchers from all over the world have provided many new treatments, one of which is CRISPR/Cas9. Today, the CRISPR/Cas9 system is mostly used for genetic modifications in various species. In addition, by using the abilities available in the CRISPR/Cas9 system, researchers can either remove or modify DNA sequences, which in this way can establish a suitable and useful treatment method for the treatment of genetic diseases that have undergone mutations. We conducted a non-systematic review of articles and study results from various databases, including PubMed, Medline, Web of Science, and Scopus, in recent years. and have investigated new treatment methods in neurodegenerative diseases with a focus on Alzheimer's disease. Then, in the following sections, the treatment methods were classified into three groups: anti-tau, anti-amyloid, and anti-APOE regimens. Finally, we discussed various applications of the CRISPR/Cas-9 system in Alzheimer's disease. Today, using CRISPR/Cas-9 technology, scientists create Alzheimer's disease models that have a more realistic phenotype and reveal the processes of pathogenesis; following the screening of defective genes, they establish treatments for this disease.

Pharmacological enhancement of cholinergic neurotransmission alleviates neuroinflammation and improves functional outcomes in a triple transgenic mouse model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Due to the multifactorial nature of the disease, involving impairment of cholinergic neurotransmission and immune system, previous attempts to find effective treatments have faced challenges. Methods: In such scenario, we attempted to investigate the effects of alpha-glyceryl-phosphoryl-choline (α-GPC), a cholinomimetic molecule, on neuroinflammation and memory outcome in the triple transgenic mouse model of AD (3xTg-AD). Mice were enrolled at 4 months of age, treated orally with α-GPC dissolved in drinking water at a concentration resulting in an average daily dose of 100 mg/kg for 8 months and sacrificed at 12 months of age. Thereafter, inflammatory markers, as well as cognitive parameters, were measured. Results: Chronic α-GPC treatment reduced accumulation of amyloid deposits and led to a substantial re-balance of the inflammatory response of resident innate immune cells, astrocytes and microglia. Specifically, fluorescent immunohistochemistry and Western blot analysis showed that α-GPC contributed to reduction of cortical and hippocampal reactive astrocytes and pro-inflammatory microglia, concurrently increasing the expression of anti-inflammatory molecules. Whereas α-GPC beneficially affect the synaptic marker synaptophysin in the hippocampus. Furthermore, we observed that α-GPC was effective in restoring cognitive dysfunction, as measured by the Novel Object Recognition test, wherein 3xTg-AD mice treated with α-GPC significantly spent more time exploring the novel object compared to 3xTg-AD untreated mice. Discussion: In conclusion, chronic treatment with α-GPC exhibited a significant anti-inflammatory activity and sustained the key function of hippocampal synapses, crucial for the maintenance of a regular cognitive status. In light of our results, we suggest that α-GPC could be exploited as a promising therapeutic approach in early phases of AD.

Protective effect of Ganoderma lucidum-fermented crop extracts against hydrogen peroxide- or ß-amyloid-induced damage in human neuronal SH-SY5Y cells.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of stacked ß-amyloid peptides in the brain and associated with the generation of oxidative stress. So far, there is no cure for AD or a way to stop its progression. Although the neuroprotective effects of Ganoderma lucidum aqueous extract and G. lucidum-derived triterpenoids and polysaccharides have been reported, the influence of G. lucidum-fermented crops on AD still lacks clarity. METHODS: This study aimed to investigate the protective effect of G. lucidum-fermented crop extracts against hydrogen peroxide- or ß-amyloid peptide (Aß25-35)-induced damage in human neuroblastoma SH-SY5Y cells. RESULTS: Various extracts of G. lucidum-fermented crops, including extract A: 10% ethanol extraction using microwave, extract B: 70˚C water extraction, and extract C: 100˚C water extraction followed by ethanol precipitation, were prepared and analyzed. Extract B had the highest triterpenoid content. Extract C had the highest total glucan content, while extract A had the highest gamma-aminobutyric acid (GABA) content. The median inhibitory concentration (IC50, mg/g) for DPPH and ABTS scavenging activity of the fermented crop extracts was significantly lower than that of the unfermented extract. Pretreatment with these extracts significantly increased the cell viability of SH-SY5Y cells damaged by H2O2 or Aß25-35, possibly by reducing cellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Moreover, extract B markedly alleviated the activity of acetylcholinesterase (AChE), which is crucial in the pathogenesis of AD. CONCLUSION: These results clearly confirmed the effects of G. lucidum-fermented crop extracts on preventing against H2O2- or Aß25-35-induced neuronal cell death and inhibiting AChE activity, revealing their potential in management of AD.

Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer's disease and related dementias.

Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer's disease (AD)-Aß plaques and neurofibrillary tangles-and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aß plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick's disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

Resveratrol: Protective Agent Against Alzheimer's Disease.

Resveratrol is a biologically active natural phenolic plant product. It has several properties which make them useful to treat the disease. In this review, we have highlighted the neuroprotective effects of resveratrol. Several available animal models have been proven to help understand the disease pathway and mechanism of action by resveratrol. In this review, we have highlighted the neuroprotective activity of resveratrol in AD, which effectively counter the neurodegenerative disease by decreasing the formation of plaques. Resveratrol is a natural plant product that is easily available, cost-effective, and possesses neuroprotective activity, which is useful for treating neurodegenerative diseases. Resveratrol presents a promising avenue for AD treatment due to its diverse neuroprotective mechanisms. Given the ongoing global challenge in treating AD, researchers have increasingly focused on exploring the therapeutic potential of resveratrol.

Fractal Analysis in Neurodegenerative Diseases.

Neurodegenerative diseases are defined by progressive nervous system dysfunction and death of neurons. The abnormal conformation and assembly of proteins is suggested to be the most probable cause for many of these neurodegenerative disorders, leading to the accumulation of abnormally aggregated proteins, for example, amyloid ß (Aß) (Alzheimer's disease and vascular dementia), tau protein (Alzheimer's disease and frontotemporal lobar degeneration), α-synuclein (Parkinson's disease and Lewy body dementia), polyglutamine expansion diseases (Huntington disease), or prion proteins (Creutzfeldt-Jakob disease). An aberrant gain-of-function mechanism toward excessive intraparenchymal accumulation thus represents a common pathogenic denominator in all these proteinopathies. Moreover, depending upon the predominant brain area involvement, these different neurodegenerative diseases lead to either movement disorders or dementia syndromes, although the underlying mechanism(s) can sometimes be very similar, and on other occasions, clinically similar syndromes can have quite distinct pathologies. Non-Euclidean image analysis approaches such as fractal dimension (FD) analysis have been applied extensively in quantifying highly variable morphopathological patterns, as well as many other connected biological processes; however, their application to understand and link abnormal proteinaceous depositions to other clinical and pathological features composing these syndromes is yet to be clarified. Thus, this short review aims to present the most important applications of FD in investigating the clinical-pathological spectrum of neurodegenerative diseases.

Aniracetam: An Evidence-Based Model for Preventing the Accumulation of Amyloid-ß Plaques in Alzheimer's Disease.

 Alzheimer's disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer's disease is characterized by the accumulation of amyloid-ß plaques (Aß), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aß has been the focus of Alzheimer's treatment and prevention research. The accumulation of Aß can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aß by increasing α-secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aß.

Correlation of Presynaptic and Postsynaptic Proteins with Pathology in Alzheimer's Disease.

Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer's disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30-50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer's pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions.

Unraveling the therapeutic efficacy of resveratrol in Alzheimer's disease: an umbrella review of systematic evidence.

CONTEXT: Resveratrol (RV), a natural compound found in grapes, berries, and peanuts, has been extensively studied for its potential in treating Alzheimer's disease (AD). RV has shown promise in inhibiting the formation of beta-amyloid plaques (Aß) and neurofibrillary tangles (NFTs), protecting against neuronal damage and oxidative stress, reducing inflammation, promoting neuroprotection, and improving the function of the blood-brain barrier (BBB). However, conflicting results have been reported, necessitating a comprehensive umbrella review of systematic reviews to provide an unbiased conclusion on the therapeutic effectiveness of RV in AD. OBJECTIVE: The objective of this study was to systematically synthesize and evaluate systematic and meta-analysis reviews investigating the role of RV in AD using data from both human and animal studies. DATA SOURCES AND EXTRACTION: Of the 34 systematic and meta-analysis reviews examining the association between RV and AD that were collected, six were included in this study based on specific selection criteria. To identify pertinent studies, a comprehensive search was conducted in English-language peer-reviewed journals without any restrictions on the publication date until October 15, 2023. The search was carried out across multiple databases, including Embase, MEDLINE (PubMed), Cochrane Library, Web of Science, and Google Scholar, utilizing appropriate terms relevant to the specific research field. The AMSTAR-2 and ROBIS tools were also used to evaluate the quality and risk of bias of the included systematic reviews, respectively. Two researchers independently extracted and analyzed the data, resolving any discrepancies through consensus. Of note, the study adhered to the PRIOR checklist. DATA ANALYSIS: This umbrella review presented robust evidence supporting the positive impacts of RV in AD, irrespective of the specific mechanisms involved. It indeed indicated that all six systematic and meta-analysis reviews unanimously concluded that the consumption of RV can be effective in the treatment of AD. CONCLUSION: RV exhibits promising potential for benefiting individuals with AD through various mechanisms. It has been observed to enhance cognitive function, reduce Aß accumulation, provide neuroprotection, protect the BBB, support mitochondrial function, facilitate synaptic plasticity, stabilize tau proteins, mitigate oxidative stress, and reduce neuroinflammation commonly associated with AD.

3-Acetyl coumarin alleviate neuroinflammatory responses and oxidative stress in aluminum chloride-induced Alzheimer's disease rat model.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability and interrupts cognitive function. Heavy metal exposure like aluminum chloride is associated with neurotoxicity linked to neuro-inflammation, oxidative stress, accumulation of amyloid plaques, phosphorylation of tau proteins associated with AD like symptoms. The objective of the present investigation was to assess the effect 3-acetyl coumarin (3AC) in a rat model of AD. Preliminary screening was performed with SWISS ADME to check for the bioavailability of 3-AC and likeness score which proved favorable. 3-AC docked against Caspase 3, NF-κß and tau protein kinase I exhibited good binding energies. Male rats were divided into six groups (n = 5). AlCl3 (100 mg/kg BW) was administered for 28 days before starting treatment to induce AD. Normal control rats received vehicle. Treatment groups received 10, 20 and 30 mg/kg 3-AC for 28 days. Rivastigmine (2 mg/kg) was the standard. Behavioral tests (EPM, MWM) were performed at 7-day intervals throughout study period. Rats showed improved spatial memory and learning in treatment groups during behavioral tests. Rats were euthanized on day 28. Inflammatory markers (IL-1ß, IL-16 and TNFα) exhibited significant improvement (p < 0.001) in treated rats. Oxidative stress enzymes (SOD, CAT, GSH, MDA) were restored. Caspase3 and NF-κß quantified through qRT-PCR also decreased significantly (p < 0.001) when compared to disease control group. Levels of acetyl cholinesterase, dopamine and noradrenaline were also restored in treated rats significantly (p < 0.001). 3-AC treatment restored neuroprotection probably because of anti-inflammatory, anti-oxidant and anti-cholinesterase potential; hence, this can be considered a promising therapeutic potential alternative.

Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues.

The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer's disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C-H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer's brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer's disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer's disease.

Chicoric Acid Ameliorated Beta-Amyloid Pathology and Enhanced Expression of Synaptic-Function-Related Markers via L1CAM in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aß) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aß1-42 and Aß plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aß1-42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aß plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aß levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models.

Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease.

Neurodegenerative diseases are an increasingly common group of diseases that occur late in life with a significant impact on personal, family, and economic life. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the major disorders that lead to mild to severe cognitive and physical impairment and dementia. Interestingly, those diseases may show onset of prodromal symptoms early after middle age. Commonly, the evaluation of these neurodegenerative diseases is based on the detection of biomarkers, where functional and structural magnetic resonance imaging (MRI) have shown a central role in revealing early or prodromal phases, although it can be expensive, time-consuming, and not always available. The aforementioned diseases have a common impact on the visual system due to the pathophysiological mechanisms shared between the eye and the brain. In Parkinson's disease, α-synuclein deposition in the retinal cells, as well as in dopaminergic neurons of the substantia nigra, alters the visual cortex and retinal function, resulting in modifications to the visual field. Similarly, the visual cortex is modified by the neurofibrillary tangles and neuritic amyloid ß plaques typically seen in the Alzheimer's disease brain, and this may reflect the accumulation of these biomarkers in the retina during the early stages of the disease, as seen in postmortem retinas of AD patients. In this light, the ophthalmic evaluation of retinal neurodegeneration could become a cost-effective method for the early diagnosis of those diseases, overcoming the limitations of functional and structural imaging of the deep brain. This analysis is commonly used in ophthalmic practice, and interest in it has risen in recent years. This review will discuss the relationship between Alzheimer's disease and Parkinson's disease with retinal degeneration, highlighting how retinal analysis may represent a noninvasive and straightforward method for the early diagnosis of these neurodegenerative diseases.

A Chronic Increase in Blood-Brain Barrier Permeability Facilitates Intraneuronal Deposition of Exogenous Bloodborne Amyloid-Beta1-42 Peptide in the Brain and Leads to Alzheimer's Disease-Relevant Cognitive Changes in a Mouse Model.

Background: Increased blood-brain barrier (BBB) permeability and amyloid-ß (Aß) peptides (especially Aß1-42) (Aß42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aß42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aß42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aß42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aß42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aß42 in animals injected with both PT and Aß42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aß42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.