Live and Heat-Inactivated Streptococcus thermophilus MN-ZLW-002 Mediate the Gut-Brain Axis, Alleviating Cognitive Dysfunction in APP/PS1 Mice.

Research on regulating brain functions with probiotics and postbiotics through the gut-brain axis is attracting attention, offering the possibility of adjuvant therapy for Alzheimer's disease (AD). Three-month-old male APP/PS1 mice were gavaged with live and heat-inactivated S. thermophilus MN-002 for three months. This study demonstrated that live and heat-inactivated S. thermophilus MN-002 improved cognitive dysfunctions in APP/PS1 mice, especially in spatial memory. However, the main effects of live S. thermophilus MN-002 directly altered the intestinal microbiota composition and increased serum IL-1ß and IL-6. Heat-inactivated S. thermophilus MN-002 increased colonic propionic acid levels and enhanced the hippocampus's antioxidant capacity. Furthermore, the changes were more obvious in the high-dose group, such as astrogliosis in the hippocampus. These results indicate that different forms and doses of the same strain, S. thermophilus MN-002, can partly improve cognitive functions in AD model mice via the gut-brain axis.

Low-Dose Radiation Therapy Impacts Microglial Inflammatory Response without Modulating Amyloid Load in Female TgF344-AD Rats.

Background: Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer's disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. Objective: As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Methods: Females were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. Results: A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. Conclusions: A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD.

The Neuro-Inflammatory Microenvironment: An Important Regulator of Stem Cell Survival in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-ß plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no "curative" drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα, CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ, CSF1R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD.

Futuristic Alzheimer's therapy: acoustic-stimulated piezoelectric nanospheres for amyloid reduction.

The degeneration of neurons due to the accumulation of misfolded amyloid aggregates in the central nervous system (CNS) is a fundamental neuropathology of Alzheimer's disease (AD). It is believed that dislodging/clearing these amyloid aggregates from the neuronal tissues could lead to a potential cure for AD. In the present work, we explored biocompatible polydopamine-coated piezoelectric polyvinylidene fluoride (DPVDF) nanospheres as acoustic stimulus-triggered anti-fibrillating and anti-amyloid agents. The nanospheres were tested against two model amyloidogenic peptides, including the reductionist model-based amyloidogenic dipeptide, diphenylalanine, and the amyloid polypeptide, amyloid beta (Aß42). Our results revealed that DPVDF nanospheres could effectively disassemble the model peptide-derived amyloid fibrils under suitable acoustic stimulation. In vitro studies also showed that the stimulus activated DPVDF nanospheres could efficiently alleviate the neurotoxicity of FF fibrils as exemplified in neuroblastoma, SHSY5Y, cells. Studies carried out in animal models further validated that the nanospheres could dislodge amyloid aggregates in vivo and also help the animals regain their cognitive behavior. Thus, these acoustic stimuli-activated nanospheres could serve as a novel class of disease-modifying nanomaterials for non-invasive electro-chemotherapy of Alzheimer's disease.

Osteocyte-derived sclerostin impairs cognitive function during ageing and Alzheimer's disease progression.

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-ß-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-ß-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-ß-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid ß (Aß) production through ß-catenin-ß-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αß production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.

Monoclonal antibody therapy for Alzheimer's disease focusing on intracerebral targets.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Due to the complexity of the disorder and the presence of the blood-brain barrier (BBB), its drug discovery and development are facing enormous challenges, especially after several failures of monoclonal antibody (mAb) trials. Nevertheless, the Food and Drug Administration's approval of the mAb aducanumab has ushered in a new day. As we better understand the disease's pathogenesis and identify novel intracerebral therapeutic targets, antibody-based therapies have advanced over the past few years. The mAb drugs targeting ß-amyloid or hyperphosphorylated tau protein are the focus of the current research. Massive neuronal loss and glial cell-mediated inflammation are also the vital pathological hallmarks of AD, signaling a new direction for research on mAb drugs. We have elucidated the mechanisms by which AD-specific mAbs cross the BBB to bind to targets. In order to investigate therapeutic approaches to treat AD, this review focuses on the promising mAbs targeting intracerebral dysfunction and related strategies to cross the BBB.

Vitamin D Reduces GABA-Positive Astrocytes in the 5xFAD Mouse Model of Alzheimer's Disease.

Background: Vitamin D has neuroprotective and immunomodulating functions that may impact glial cell function in the brain. Previously, we reported molecular and behavioral changes caused by deficiency and supplementation of vitamin D in an Alzheimer's disease (AD) mouse model. Recent studies have highlighted reactive astrocytes as a new therapeutic target for AD treatment. However, the mechanisms underlying the therapeutic effects of vitamin D on the glial cells of AD remain unclear. Objective: To investigate the potential association between vitamin D deficiency/supplementation and the pathological progression of AD, including amyloid-ß (Aß) pathology and reactive astrogliosis. Methods: Transgenic hemizygous 5XFAD male mice were subjected to different dietary interventions and intraperitoneal vitamin D injections to examine the effects of vitamin D deficiency and supplementation on AD. Brain tissue was then analyzed using immunohistochemistry for Aß plaques, microglia, and astrocytes, with quantifications performed via ImageJ software. Results: Our results demonstrated that vitamin D deficiency exacerbated Aß plaque formation and increased GABA-positive reactive astrocytes in AD model mice, while vitamin D supplementation ameliorated these effects, leading to a reduction in Aß plaques and GABA-positive astrocytes. Conclusions: Our findings highlight the significant impact of vitamin D status on Aß pathology and reactive astrogliosis, underscoring its potential role in the prevention and treatment of AD. This study provides the first in vivo evidence of the association between vitamin D and reactive astrogliosis in AD model mice, indicating the potential for targeting vitamin D levels as a novel therapeutic approach for AD.

Computational insights into the cross-talk between medin and Aß: implications for age-related vascular risk factors in Alzheimer's disease.

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-ß (Aß) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aß results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aß-two intrinsically disordered proteins-is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aß and medin were aggregation prone and their mixture tended to form ß-sheet-rich hetero-aggregates. The formation of Aß-medin hetero-aggregates did not hinder Aß and medin from recruiting additional Aß and medin peptides to grow into larger ß-sheet-rich aggregates. The ß-barrel oligomer intermediates observed in the self-aggregations of Aß and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aß fibrils could recruit isolated medin monomers to form elongated ß-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aß and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aß. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.

Non-coding RNAs in Regulation of Protein Aggregation and Clearance Pathways: Current Perspectives Towards Alzheimer's Research and Therapy.

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 45.0 million people worldwide and ranking as the fifth leading cause of mortality. AD is identified by neurofibrillary tangles (NFTs), which include abnormally phosphorylated tau-protein and amyloid protein (amyloid plaques). Peptide dysregulation is caused by an imbalance between the production and clearance of the amyloid-beta (Aß) and NFT. AD begins to develop when these peptides are not cleared from the body. As a result, understanding the processes that control both normal and pathological protein recycling in neuronal cells is critical. Insufficient Aß and NFT clearance are important factors in the development of AD. Autophagy, lysosomal dysfunction, and ubiquitin-proteasome dysfunction have potential roles in the pathogenesis of many neurodegenerative disorders, particularly in AD. Modulation of these pathways may provide a novel treatment strategy for AD. Non-coding RNAs (ncRNAs) have recently emerged as important biological regulators, with particular relevance to the emergence and development of neurodegenerative disorders such as AD. ncRNAs can be used as potential therapeutic targets and diagnostic biomarkers due to their critical regulatory functions in several biological processes involved in disease development, such as the aggregation and accumulation of Aß and NFT. It is evident that ncRNAs play a role in the pathophysiology of AD. In this communication, we explored the link between ncRNAs and AD and their regulatory mechanisms that may help in finding new therapeutic targets and AD medications.

Salvianolic acid B exerts protective effects against Aß-induced neuroinflammation through the inhibition of NLRP3 inflammasome activation and switching of M1/M2 polarization.

BACKGROUND: Salvianolic acid B (SalB) is a bioactive extract of Salvia miltiorrhiza with the ability to ameliorate amyloid beta (Aß)-induced neuronal degeneration and neuroinflammation in Alzheimer's disease (AD). However, the underlying mechanisms of this action have not been elucidated. Herein, we aimed to investigate whether the neuroprotective effect of SalB is attributable to the modulation of microglial polarization and NLRP3 inflammasome-mediated neuroinflammation. METHODS: Based on the TMT-labeled proteomics analysis, immunofluorescence, western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were employed to investigate the effects of SalB on neuroinflammation in Aß1-42-stimulated BV2 microglia cells. RESULTS: At the proteomic level, a total of 6631 proteins were quantified, and of these, 104 were significantly influenced under Aß1-42 treatment. The expression of 36 Aß1-42-induced differentially expressed proteins were significantly recovered by SalB treatment (13 upregulated and 23 downregulated). NLRP3 was significantly recovered and was identified as one of the hub proteins. Consistent with the result of the proteomic analysis, western blot and qRT-PCR demonstrated that SalB reduced Aß1-42-induced NLRP3 upregulation at both the protein and mRNA levels. In addition, SalB significantly blocked M1 microglia polarization, enhanced M2 microglial polarization, and inhibited the production of caspase-1 and interleukin-1ß in BV2 microglia cells. CONCLUSION: our study demonstrated, for the first time, that the anti-inflammatory effects of SalB were mediated by the regulation of NLRP3 activation and promotion of microglial M2 polarization, indicating the potential of SalB as a novel therapeutic candidate for AD.

The FDA-approved anti-amyloid-ß monoclonal antibodies for the treatment of Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Alzheimer's disease (AD) is a worldwide public health problem and is difficult to cure. Drugs aimed at slowing the progression of the disease have been developed, with the Food and Drug Administration (FDA) granting accelerated approval for aducanumab on June 21, 2021 and a new accelerated approval for lecanemab on January 22, 2023. We performed this systematic review and meta-analysis to assess the efficacy and safety of FDA-approved anti-amyloid-ß (anti-Aß) monoclonal antibodies (mabs) for the treatment of AD. METHOD: PubMed, Embase, and Cochrane Library were systematically searched to identify relevant studies published before May 2023. Efficacy outcomes included Aß, neuroimaging, and biomarker outcomes. Safety outcomes included amyloid-related imaging abnormalities with edema or effusions (ARIA-E) and ARIA with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (ARIA-H). Review Manager 5.4 software was used to assess the data. The standard mean differences (SMDs) or odds ratio (OR) with 95% confidence interval (95% CI) were analyzed and calculated with a random effect model or a fixed effect model. RESULT: Overall, 4471 patients from 6 randomized controlled trials (RCTs), with 2190 patients in the treatment group and 2281 patients in the placebo group meeting the inclusion criteria. FDA-approved anti-Aß mabs showed statistically significant improvements in clinical outcomes, including CDR-SB (P = 0.01), ADCS-ADL-MCI (P = 0.00003), ADCOMS (P < 0.00001), ADAS-Cog (P < 0.00001). Moreover, FDA-approved anti-Aß mabs increased cerebrospinal fluid (CSF) Aß1-42 (P = 0.002) and plasma Aß42/40 ratios (P = 0.0008). They also decreased CSF P-Tau (P < 0.00001), CSF T-Tau (P < 0.00001), and plasma p-tau181 (P < 0.00001). FDA-approved anti-Aß mabs perform neuroimaging changes in amyloid Positron Emission Tomography Standardized Uptake Value ratio (PET SUVr) (P < 0.00001). However, compared with placebo, FDA-approved anti-Aß mabs had higher risk of ARIA-E (P < 0.00001) and ARIA-H (P < 0001). CONCLUSION: FDA-approved anti-Aß mabs have a role in slowing disease progression in patients with AD, at the cost of an increased probability of side effects.

Novel anti-amyloid-beta (Aß) monoclonal antibody lecanemab for Alzheimer's disease: A systematic review.

BACKGROUND: Lecanemab is the latest monoclonal antibody that targets beta-amyloid approved exclusively for treatment of Alzheimer's disease with mild cognitive impairment or mild dementia. This article aims to provide a systematic review of the efficacy, and safety of lecanemab in slowing clinical decline in Alzheimer's disease. METHODS: A comprehensive search of various databases, including the National Institute of Health clinical trials registry, PubMed, and the Cochrane library, was conducted until July 2023 using the keywords lecanemab, BAN2401, and Alzheimer's disease. Additionally, conference abstracts listed in the Cochrane database (including Embase) and drug information from the US Food and Drug Administration (FDA) label were examined. Only clinical trials published in the English language were considered. In total, 107 articles were retrieved, and after thorough evaluation, three randomized, double-blind, multicenter clinical trials involving 2729 participants were included in the analysis. RESULTS: The FDA approved lecanemab for Alzheimer's disease in January 2023 which acts as a novel disease-modifying anti-amyloid-beta (Aß) human monoclonal antibody and is administered intravenously. Based on the clinical trials included in this review, lecanemab was found efficacious in reducing the accumulation of beta-amyloid and slowing down the cognitive decline and it was well tolerated. Lecanemab had a statistically significant change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), Alzheimer's Disease Assessment Scale (ADAScog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and reductions in brain amyloid burden. The most common treatment-emergent adverse events were headache, infusion-related reactions, and Amyloid related imaging abnormalities-edema. CONCLUSIONS: Lecanemab therapy led to a substantial decrease in amyloid plaques and a noticeable slowing of clinical decline. The findings suggest a meaningful connection between the reduction in amyloid and the positive impact on patients' clinical outcomes, hinting at potential disease-modifying effects.

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

There are few treatments that slow neurodegeneration in Alzheimer's disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood-brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aß) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). In vitro, trontinemab showed a similar binding affinity to fibrillar Aß40 and Aß plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, Macaca fascicularis), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4-18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial.

Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update.

Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.

Self-Assembly Driven Formation of Functional Ultralong "Artificial Fibers" to Mitigate the Neuronal Damage Associated with Alzheimer's Disease.

Fibrillation of amyloid beta (Aß) is the key event in the amyloid neurotoxicity process that induces a chain of toxic events including oxidative stress, caspase activation, poly(ADP-ribose) polymerase cleavage, and mitochondrial dysfunction resulting in neuronal loss and memory decline manifesting as clinical dementia in humans. Herein, we report the development of a novel, biologically active supramolecular probe, INHQ, and achieve functional nanoarchitectures via a self-assembly process such that ultralong fibers are achieved spontaneously. With specifically decorated functional groups on INHQ such as imidazole, hydroxyquinoline, hydrophobic chain, and hydroxyquinoline molecules, these ultralong fibers coassembled efficiently with toxic Aß oligomers and mitigated the amyloid-induced neurotoxicity by blocking the aforementioned biochemical events leading to neuronal damage in mice. These functional ultralong "Artificial Fibers" morphologically resemble the amyloid fibers and provide a higher surface area of interaction that improves its clearance ability against the Aß aggregates. The efficacy of this novel INHQ molecule was ascertained by its high ability to interact with Aß. Moreover, this injectable, ultralong INHQ functional "artificial fiber" translocates through the blood-brain barrier and successfully attenuates the amyloid-triggered neuronal damage and pyknosis in the cerebral cortex of wild-type mouse. Utilizing various spectroscopic techniques, morphology analysis, and in vitro, in silico, and in vivo studies, these ultralong INHQ fibers are proven to hold great promise for treating neurological disorders at all stages with a potential to replace the existing medications, reduce complications in the brain, and eradicate the amyloid-triggered neurotoxicity implicated in numerous disorders in human through a rare synergistic mechanism.

Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers.

Targeted therapies for prostate, breast, and ovarian cancers are based on their activity against primary tumors rather than their anti-metastatic activity. Consequently, there is an urgent need for new agents targeting the metastatic process. Emerging evidence correlates in vitro and in vivo cancer invasion and metastasis with increased activity of the proteases mesotrypsin (prostate and breast cancer) and kallikrein 6 (KLK6; ovarian cancer). Thus, mesotrypsin and KLK6 are attractive putative targets for therapeutic intervention. As potential therapeutics for advanced metastatic prostate, breast, and ovarian cancers, we report novel mesotrypsin- and KLK6-based therapies, based on our previously developed mutants of the human amyloid ß-protein precursor Kunitz protease inhibitor domain (APPI). These mutants, designated APPI-3M (prostate and breast cancer) and APPI-4M (ovarian cancer), demonstrated significant accumulation in tumors and therapeutic efficacy in orthotopic preclinical models, with the advantages of long retention times in vivo, high affinity and favorable pharmacokinetic properties. The applicability of the APPIs, as a novel therapy and for imaging purposes, is supported by their good safety profile and their controlled and scalable manufacturability in bioreactors.

Evaluation of Efficacy and Safety Using Low Dose Radiation Therapy with Alzheimer's Disease: A Protocol for Multicenter Phase II Clinical Trial.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-ß (Aß) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. OBJECTIVE: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. METHODS: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aß42/Aß40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer's Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. CONCLUSIONS: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD.

Alzheimer's Disease and Sex-Dependent Alterations in the Striatum: A Lesson from a Mouse Model.

In the last years, many clinical studies highlighted sex-specific differences in the pathophysiology of Alzheimer's disease (AD). The recent paper published in the Journal of Alzheimer's Disease shows the influence of sex on amyloid-ß plaque deposition, behavior, and dopaminergic signaling in the 5xFAD mouse model of AD, with worse alterations in female mice. This commentary focuses on the importance of recognizing sex as a key variable to consider for a more precise clinical practice, with the challenge to develop sex-specific therapeutic interventions in neurodegenerative diseases such as AD.

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.

Background: The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

Apoptosis in Alzheimer's disease: insight into the signaling pathways and therapeutic avenues.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and amyloid-ß (Aß) protein resulting in synaptic loss and apoptosis. Aß and tau deposition trigger apoptotic pathways that result in neuronal death. Apoptosis is considered to be responsible for manifestations associated with AD under pathological conditions. It regulates via extrinsic and intrinsic pathways. It activates various proteins including Bcl-2 family proteins like Bax, Bad, Bid, Bcl-XS, Bcl-XL and caspases comprising of initiator, effector and inflammatory caspases carried out through a cascade of events that finally lead to cell disintegration. The apoptotic elements interact with trophic factors, signaling molecules including Ras-ERK, JNK, GSK-3ß, BDNF/TrkB/CREB and PI3K/AKT/mTOR. Ras-ERK signaling is involved in the progression of cell cycle and apoptosis. JNK pathway is also upregulated in AD which results in decreased expression of anti-apoptotic proteins. JAK-STAT triggers caspase-3 mediated apoptosis leading to neurodegeneration. The imbalance between autophagy and apoptosis is regulated by PI3K/Akt/mTOR pathway. GSK-3ß is involved in the stimulation of pro-apoptotic factors resulting in dysregulation of apoptosis. Drugs like filgrastim, epigallocatechin gallate, curcumin, nicergoline and minocycline are under development which target these pathways and modulate the disease condition. This study sheds light on apoptotic pathways that are cardinal for neuronal survival and perform crucial role in the occurrence of AD along with the trends in therapeutics targeting apoptosis induced AD. To develop prospective treatments for AD, it is desirable to elucidate potential targets including restoration apoptotic balance, regulation of caspases, Bcl-2 and other crucial proteins involved in apoptosis mediated AD.