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Alzheimer's disease (AD) stands as the predominant contributor to dementia cases. The ongoing developments in our understanding of its pathogenesis have sparked the interest of researchers, driving them to explore innovative treatment approaches. Existing therapies incorporating cholinesterase inhibitors and/or NMDA antagonists have shown limited improvement in alleviating symptoms. This, in turn, highlights the urgency for the pursuit of more effective therapeutic options. Given the annual rise in the number of individuals affected by dementia, it is imperative to allocate resources and efforts towards the exploration of novel therapeutic options. This review aims to provide a comprehensive overview of the AD-related hypotheses, along with the computational approaches employed in research within each hypothesis. In this comprehensive review, the authors shed light on using various computational tools, including diverse case studies, in the pursuit of finding efficacious treatments for AD. The development of more sophisticated diagnostic techniques is crucial, enabling early detection and intervention in the battle against this challenging condition. The potential treatments investigated in this analysis are poised to assume ever more significant functions in both preventing and treating AD, ultimately enhancing the management of the condition and the overall well-being of individuals affected by AD.

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Familial Alzheimer's disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aß), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 µM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aß by -69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by -33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by -25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by -29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by -33, -86, and -78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aß (Vina Score -6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

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Familial Alzheimer's disease (FAD) is a chronic neurological condition that progresses over time. Currently, lacking a viable treatment, the use of multitarget medication combinations has generated interest as a potential FAD therapy approach. In this study, we examined the effects of 4-phenylbutyric acid (4-PBA) and methylene blue (MB) either separately or in combination on PSEN1 I416T cholinergic-like neuron cells (ChLNs), which serve as a model for FAD. We found that MB was significantly efficient at reducing the accumulation of intracellular Aß, phosphorylation of TAU Ser202/Thr205, and increasing Δψm, whereas 4-PBA was significantly efficient at diminishing oxidation of DJ-1Cys106-SH, expression of TP53, and increasing ACh-induced Ca2+ influx. Both agents were equally effective at blunting phosphorylated c-JUN at Ser63/Ser73 and activating caspase 3 (CASP3) into cleaved caspase 3 (CC3) on mutant cells. Combination of MB and 4-PBA at middle (0.1, 1) concentration significantly reduced iAß, p-TAU, and oxDJ-1 and augmented the ACh-induced Ca2+ influx compared to combined agents at low (0.05, 0.5) or high (0.5, 5) concentration. However, combined MB and 4-PBA were efficient only at dropping DJ-1Cys106-SO3 and increasing ACh-induced Ca2+ inward in mutant ChLNs. Our data show that the reagents MB and 4-PBA alone possess more than one action (e.g., antiamyloid, antioxidant, anti-TAU, antiapoptotic, and ACh-induced Ca2+ influx enhancers), that in combination might cancel or diminish each other. Together, these results strongly argue that MB and 4-PBA might protect PSEN1 I416T ChLNs from Aß-induced toxicity by working intracellularly as anti-Aß and anti-Tau agents, improving Δψm and cell survival, and extracellularly, by increasing ACh-induced Ca2+ ion influx. MB and 4-PBA are promising drugs with potential for repurposing in familial AD.

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Alzheimer's disease (AD) stands as the most prevalent form of neuropsychiatric disorder among the elderly population, impacting a minimum of 50 million individuals worldwide. Current pharmacological treatments rely on the prescribing cholinesterase inhibitors and memantine. However,recently anecdotal findings based on low-quality real-world data had prompted physicians, patients, and their relatives to consider the use of cannabinoids, especially Cannabidiol (CBD), for alleviating of AD symptoms. CBD the primary non-psychotomimetic compound found in the Cannabis sp. plant, exhibits promising therapeutic potential across various clinical contexts. Pre-clinical and in vitro studies indicate that CBD could mitigate cognitive decline and amyloid-beta-induced neurodegeneration by modulating oxidative stress and neuroinflammation. In addition, CBD demonstrates significant effects in promoting neuroplasticity, particularly in brain regions such as the hippocampus. However, the available clinical evidence presents conflicting results, and no randomized placebo-controlled trials have been published to date. In conclusion, although pre-clinical and in vitro studies offer encouraging insights into the potential benefits of CBD in AD models, new and well-designed clinical trials are imperative to ascertain the clinical relevance of CBD use in the management of AD symptoms, especially in comparison to conventional treatments.

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Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAß; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 µM), CU (10 µM), or SP (1 µM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 µM) concentration was efficient in diminishing the iAß, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAß compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAß-induced ChLN damage in FAD.

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Alzheimer's disease (AD) represents the most common type of dementia. A crucial mechanism attributed to its development is amyloid beta (Aß) dynamics dysregulation. The extent to which exercise can modulate this phenomenon is uncertain. The aim of this study was to summarize the existing literature evaluating this issue. A comprehensive systematic search was performed in Pubmed, Scopus, Embase, Web of Science, and SciELO databases and completed in August 2023, aiming to identify randomized controlled trials investigating the effect of exercise upon Aß-related pathology. The keywords "exercise" and "amyloid beta", as well as all their equivalents and similar terms, were used. For the analysis, the negative or positive dementia status of the subjects was initially considered and then the soluble amyloid precursor protein (sAPP) components and Aß fragments separately. A meta-analysis was performed and involved eight studies (moderate-to-high quality) and 644 assessments, which were 297 for control and 347 for exercise. No overall effect favoring exercise interventions was observed for both negative (SMD95%=0,286 [-0,131; 0,704]; p = 0,179) or positive AD dementia status (SMD95%=0,110 [-0,155; 0,375]; p = 0,416). The absence of an overall effect favoring exercise interventions was also found for Aß peptides (SMD95%=0,226 [-0,028; 0,480]; p = 0,081) and for sAPP components (SMD95%=-0,038 50 [-0,472; 0,396]; p = 0,863) levels. Our findings suggest that exercise interventions do not improve Aß-related pathology in both healthy individuals and individuals with dementia (SMD95%=0,157 [-0,059; 0,373]; p = 0,155), indicating that the beneficial effects of exercise for AD reported in previous studies are related to other mechanistic effects rather than direct amyloid effects (PROSPERO registration number: CRD42023426912).

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Abstract Background Alzheimer's disease (AD) was described in 1907, and since then it changed from a relatively rare condition to one of the most prevalent diseases. Objective To describe the evolution of the notions of dementias and AD, and to investigate the reasons for the increase in scientific interest in AD. Methods A historical analysis was carried out on knowledge about dementia, the site of mental activity, the relationships between brain diseases and mental activity, and on the advances in research about AD, since its discovery until the publication of the amyloid cascade hypothesis in 1992. A search was carried out in the National Library of Medicine (PubMed) for scientific articles that included the terms dementia or AD over 50 years, from 1972 to 2021. Results The scientific research on AD increased from 615 papers with the term AD in the first decade (1972-1981), to 100,028 papers in the last decade (2012-2021): an increase of 162.6 times whereas publications with the term dementia increased 28.6 times in the same period. In the 1960s and 1970s, a consensus was reached that AD is responsible for the majority of cases of dementia previously known as senile dementia. In the 1980s, beta-amyloid peptide was identified in the core of the senile plaque, hyperphosphorylated tau protein was found in neurofibrillary tangles, and a mutation was discovered in a hereditary form of AD. Conclusion The expansion of the concept of AD to include senile dementia, and the discoveries that occurred in the 1980s greatly expanded research in AD.

Resumo Antecedentes A doença de Alzheimer (DA) foi descrita em 1907 e, desde então, deixou de ser relativamente rara para se tornar uma das doenças mais prevalentes. Objetivo Descrever a evolução das noções sobre demências e DA e investigar as razões do aumento do interesse científico pela DA. Métodos Foi realizada uma análise histórica dos conhecimentos sobre demência, o local da atividade mental, as relações entre doenças cerebrais e a atividade mental, e sobre os avanços na pesquisa sobre a DA, desde a sua descoberta até a publicação da hipótese da cascata amiloide em 1992. Foi realizada uma busca na Biblioteca Nacional de Medicina dos Estados Unidos da América (PubMed) por artigos científicos que incluíssem os termos demência ou DA nos 50 anos, de 1972 a 2021. Resultados A pesquisa científica sobre DA aumentou de 615 artigos com o termo doença de Alzheimer na primeira década (1972-1981), para 100.028 artigos na última década (2012-2021): um aumento de 162,6 vezes enquanto as publicações com o termo demência aumentaram 28,6 vezes no mesmo período. Nas décadas de 1960 e 1970, chegou-se a um consenso de que a DA é responsável pela maioria dos casos de demência, anteriormente conhecida como demência senil. Na década de 1980, o peptídeo beta-amiloide foi identificado no núcleo da placa senil, a proteína tau hiperfosforilada foi encontrada em emaranhados neurofibrilares e uma mutação foi descoberta em uma forma hereditária de DA. Conclusão A expansão do conceito de DA para incluir a demência senil e as descobertas ocorridas na década de 1980 ampliaram enormemente a pesquisa em DA.

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Hippocampal neuronal activity generates dendritic and somatic Ca2+ signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AßOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer's disease, generate aberrant Ca2+ signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AßOs concentrations on activity-generated nuclear Ca2+ signals and on the Ca2+-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABAA receptor blocker gabazine (GBZ), and nuclear Ca2+ signals were measured in AßOs-treated or control neurons transfected with a genetically encoded nuclear Ca2+ sensor. Incubation (6 h) with AßOs significantly reduced the nuclear Ca2+ signals and the enhanced phosphorylation of cyclic AMP response element-binding protein (CREB) induced by GBZ. Likewise, incubation (6 h) with AßOs significantly reduced the GBZ-induced increases in the mRNA levels of neuronal Per-Arnt-Sim domain protein 4 (Npas4), brain-derived neurotrophic factor (BDNF), ryanodine receptor type-2 (RyR2), and the antioxidant enzyme NADPH-quinone oxidoreductase (Nqo1). Based on these findings we propose that AßOs, by inhibiting the generation of activity-induced nuclear Ca2+ signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes.

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This Review emphasizes the impact of APOE4-the most significant genetic risk factor for Alzheimer's disease (AD)-on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles' effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden-as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs-in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aß42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer's Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aß42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer's Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

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Introduction: Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to AD. Most studies, however, have been conducted with aerobic exercises, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD. Similar to AD patients, double-transgenic APPswe/PS1dE9 (APP/PS1) mice exhibit Αß plaques in the cortex and hippocampus, hyperlocomotion, memory deficits, and exacerbated inflammatory response. Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice. Methods: For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (CTRL), were distributed into three groups: CTRL, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aß plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay. Results: APP/PS1 transgenic sedentary mice showed increased hippocampal Aß plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aß alterations to the CTRL levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Despite these alterations, no memory impairment was observed in APP/PS1 mice in the novel object recognition test. Discussion: Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

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The multifactorial nature of Alzheimer's disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD-associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE-induced ß-amyloid peptide (Aß) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL-NH2 ) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC50 value against hAChE reported for a peptide (0.99±0.02 µM) and inhibited 94.2 %±1.2 of AChE-induced Aß aggregation at 10 µM. Furthermore, it inhibited hBChE (IC50 , 15.44±0.91 µM), showed no in vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe2+ chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors.

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In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration, we aimed at revisiting the infectious hypothesis of Alzheimer's disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration. We wondered how SARS-CoV-2 could be related to the amyloid-ß cascade and how it could lead to the pathological hallmarks of the disease. We also predict a paradigm change in clinical medicine, which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer's disease.

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Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.

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Current research efforts at neurological diseases have focused on identifying novel biomarkers to aid in diagnosis, to provide accurate prognostic information, and to monitor disease progression. This study presents the direct coupling of fiber-in-tube solid-phase microextraction to tandem mass spectrometry as a reliable method to determine amyloid beta peptides (Aß38, Aß40, and Aß42) as biomarkers for Alzheimer's disease in cerebrospinal fluid (CSF) samples. To obtain the biocompatible fiber-in-tube SPME capillary, a PEEK tube segment was longitudinally packed with fine fibers [nitinol wires coated with a zwitterionic polymeric ionic liquid], to act as selective extraction medium. The fiber-in-tube SPME-MS/MS method integrated analyte extraction/enrichment and sample cleanup (exclusion of interferents) into one step. The method provided lower limits of quantification (LLOQ: 0.2 ng mL-1 for Aß38 and 0.1 ng mL-1 for Aß40 and Aß42), high precision (CV lower than 11.6%), and high accuracy (relative standard deviation lower than 15.1%). This method was successfully applied to determine Aß peptides in CSF samples obtained from AD patients (n = 8) and controls (healthy volunteers, n = 10). Results showed that Aß42 levels in the CSF samples obtained from AD patients were significantly lower compared to healthy controls (p < 0.05). On the basis of the ROC analysis results, the Aß42/Aß40 ratio (AUC = 0.950, p < 0.01; 95%) performed significantly better than Aß42 alone (AUC = 0.913, p < 0.01; 95%) in discriminating between AD patients and healthy controls and presented better diagnostic ability for AD. The novelties of this study are not only related to evaluating Aß peptides as AD biomarkers, but also to demonstrating direct online coupling of fiber-in-tube SPME with MS/MS as a quantitative high-throughput method for bioanalysis.

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Alzheimer's disease (AD) is considered the most frequent neurodegenerative disorder worldwide, compromising cognitive function in patients, with an average incidence of 1-3% in the open population. Protein aggregation into amyloidogenic plaques and neurofibrillary tangles, as well as neurodegeneration in the hippocampal and cortical areas, represent the neuropathological hallmarks of this disorder. Mechanisms involved in neurodegeneration include protein misfolding, augmented apoptosis, disrupted molecular signaling pathways and axonal transport, oxidative stress, inflammation, and mitochondrial dysfunction, among others. It is precisely through a disrupted energy metabolism that neural cells trigger toxic mechanisms leading to cell death. In this regard, the study of mitochondrial dynamics constitutes a relevant topic to decipher the role of mitochondrial dysfunction in neurological disorders, especially when considering that amyloid-beta peptides can target mitochondria. Specifically, the amyloid beta (Aß) peptide, known to accumulate in the brain of AD patients, has been shown to disrupt overall mitochondrial metabolism by impairing energy production, mitochondrial redox activity, and calcium homeostasis, thus highlighting its key role in the AD pathogenesis. In this work, we review and discuss recent evidence supporting the concept that mitochondrial dysfunction mediated by amyloid peptides contributes to the development of AD.

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Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to ß-secretase (BACE), glycogen synthase kinase 3ß (GSK3ß), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1 mg/kg) administration for 45 days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aß) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.

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Alzheimer's disease (AD) was first identified more than 100 years ago, yet aspects pertaining to its origin and the mechanisms underlying disease progression are not well known. To this date, there is no therapeutic approach or disease-modifying drug that could halt or at least delay disease progression. Until recently, glial cells were seen as secondary actors in brain homeostasis. Although this view was gradually refuted and the relevance of glial cells for the most diverse brain functions such as synaptic plasticity and neurotransmission was vastly proved, many aspects of its functioning, as well as its role in pathological conditions, remain poorly understood. Metabotropic glutamate receptors (mGluRs) in glial cells were shown to be involved in neuroinflammation and neurotoxicity. Besides its relevance for glial function, glutamatergic receptors are also central in the pathology of AD, and recent studies have shown that glial mGluRs play a role in the establishment and progression of AD. AD-related alterations in Ca2+ signalling, APP processing, and Aß load, as well as AD-related neurodegeneration, are influenced by glial mGluRs. However, different types of mGluRs play different roles, depending on the cell type and brain region that is being analysed. Therefore, in this review, we focus on the current understanding of glial mGluRs and their implication in AD, providing an insight for future therapeutics and identifying existing research gaps worth investigating.

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Introduction: The development of new materials and tools for radiology is key to the implementation of this diagnostic technique in clinics. In this work, we evaluated the differential accumulation of peptide-functionalized GNRs in a transgenic animal model (APPswe/PSENd1E9) of Alzheimer's disease (AD) by computed tomography (CT) and measured the pharmacokinetic parameters and bioaccumulation of the nanosystem. Methods: The GNRs were functionalized with two peptides, Ang2 and D1, which conferred on them the properties of crossing the blood-brain barrier and binding to amyloid aggregates, respectively, thus making them a diagnostic tool with great potential for AD. The nanosystem was administered intravenously in APPswe/PSEN1dE9 model mice of 4-, 8- and 18-months of age, and the accumulation of gold nanoparticles was observed by computed tomography (CT). The gold accumulation and biodistribution were determined by atomic absorption. Results: Our findings indicated that 18-month-old animals treated with our nanosystem (GNR-D1/Ang2) displayed noticeable differences in CT signals compared to those treated with a control nanosystem (GNR-Ang2). However, no such distinctions were observed in younger animals. This suggests that our nanosystem holds the potential to effectively detect AD pathology. Discussion: These results support the future development of gold nanoparticle-based technology as a more effective and accessible alternative for the diagnosis of AD and represent a significant advance in the development of gold nanoparticle applications in disease diagnosis.

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Background: Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid ß peptide generated from the amyloid-ß precursor protein (APP) via cleavages by ß- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation. Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds. Results: Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation. Conclusions: AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aß1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a-v) were evaluated by docking simulations as inhibitors of AChE and Aß1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aß1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski's rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aß1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aß1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.

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