Therapeutic Strategy For Alzheimer's Disease Research Articles

Targeting Epac2 and GluA3-containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease

Targeting Epac2 and GluA3-containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease

Positron Emission Tomography/Computed Tomography Imaging in Therapeutic Clinical Trials in Alzheimer's Disease: AnOverview of the Current State of the Artof Research.

The integration of positron emission tomography/computed tomography (PET/CT) has revolutionized the landscape of Alzheimer's disease (AD) research and therapeutic interventions. By combining structural and functional imaging, PET/CT provides a comprehensive understanding of disease pathology and response to treatment assessment. PET/CT, particularly with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), facilitates the visualization of glucose metabolism in the brain, enabling early diagnosis, staging, and monitoring of neurodegenerative disease progression. The advent of amyloid and tau PET imaging has further propelled the field forward, offering invaluable tools for tracking pathological hallmarks, assessing treatment response, and predicting clinical outcomes. While some therapeutic interventions targeting amyloid plaque load showed promising results with the reduction of cerebral amyloid accumulation over time, others failed to demonstrate a significant impact of anti-amyloid agents for reducing the amyloid plaques burden in AD brains. Tau PET imaging has conversely fueled the advent of disease-modifying therapeutic strategies in AD by supporting the assessment of neurofibrillary tangles of tau pathology deposition over time. Looking ahead, PET imaging holds immense promise for studying additional targets such as neuroinflammation, cholinergic deficit, and synaptic dysfunction. Advances in radiotracer development, dedicated brain PET/CT scanners, and Artificial Intelligence-powered software are poised to enhance the quality, sensitivity, and diagnostic power of molecular neuroimaging. Consequently, PET/CT remains at the forefront of AD research, offering unparalleled opportunities for unravelling the complexities of the disease and advancing therapeutic interventions, although it is not yet enough alone to allow patients' recruitment in therapeutic clinical trials.

Tyrosine modifications of insulin-degrading enzyme enable favorable control of substrate specificity for both Alzheimer’s disease and type-2 diabetes mellitus

Insulin-degrading enzyme (IDE) cleaves amyloid beta (Aβ), insulin, and other bioactive peptides. Because Aβ and insulin are closely related to Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM), respectively, IDE is a candidate drug target for treating both AD and T2DM. However, the activity of IDE has opposing effects, including decreasing AD risk by degrading Aβ and increasing T2DM risk by degrading insulin. The opposed substrate specificity is associated with the exo- and active sites containing Tyr314 and Tyr831 residues, the plausible modification targets for controlling substrate specificity. In this study, we used a tyrosine-specific modification regent, Cookson reagent (4-phenyl-1,2,4-triazoline-3,5-dione, PTAD), for IDE and examined the degradation activities on Aβ40 and insulin. Fifteen tyrosine residues, including Tyr314 and Tyr831, were modified by PTAD. After incubation with PTAD-modified IDE for 3 days, insulin remained intact, whereas Aβ40 was completely degraded. This favorable change of substrate specificity was also observed in the mixture of Aβ40 and insulin, suggesting that tyrosine modification of IDE might be a therapeutic strategy for AD and T2DM.

Network Pharmacology, Molecular Dynamics and In Vitro Assessments of Indigenous Herbal Formulations for Alzheimer’s Therapy

Alzheimer’s disease (AD) is an age-associated neurodegenerative condition marked by amyloid plaques, synaptic dysfunction, and neuronal loss. Besides conventional medical care, herbal therapies, both raw and refined, have attracted researchers for their potential therapeutic effects. As a proof-of-concept, our study combined HPLC-DAD analysis of bioactive constituents, network pharmacology, molecular dynamics (MD), molecular docking, post-MD analysis, and experimental verification to investigate the mechanisms of crude drug formulations as a therapeutic strategy for AD. We identified nine bioactive compounds targeting 188 proteins and 1171 AD-associated genes. Using a Venn diagram, we found 47 overlapping targets, forming “herb-compound-target (HCT)” interaction networks and a protein‒protein interaction (PPI) network. Simulations analyzed binding interactions among the three core targets and their compounds. MD assessed the stability of the best-ranked poses and beneficial compounds for each protein. Among the top 22 hub genes, AChE, BChE, and MAO, ranked 10, 14, and 34, respectively, were selected for further analysis. Two tetraherbal formulations, Form A and Form B, showed notable activity against AChE. Form A exhibited significant (p < 0.0001) inhibitory activity (IC50 = 114.842 ± 2.084 µg/mL) compared to Form B (IC50 = 142.829 ± 4.258 µg/mL), though weaker than galantamine (IC50 = 27.950 ± 0.122 µg/mL). Form B had significant inhibitory effects on BChE (IC50 = 655.860 ± 32.812 µg/mL) compared to Form A (IC50 = 679.718 ± 20.656 µg/mL), but lower than galantamine (IC50 = 23.126 ± 0.683 µg/mL). Both forms protected against Fe2+-mediated brain injury by inhibiting MAO. Docking identified quercetin (−10.2 kcal/mol) and myricetin (−10.1 kcal/mol) for AChE; rutin (−10.6 kcal/mol) and quercetin (−9.7 kcal/mol) for BChE; and kaempferol (−9.1 kcal/mol) and quercetin (−8.9 kcal/mol) for MAO. These compounds were thermodynamically stable based on MD analysis. Collectively, the results offer a scientific rationale for the use of these specifically selected medicinal herbs as AD medications.

Glutamate Transporter 1 as a Novel Negative Regulator of Amyloid β.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting the GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

Agonistes des récepteurs GLP-1 dans la maladie d’Alzheimer : Potentiel thérapeutique et mécanismes d’action

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by progressive cognitive decline and neuronal dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for the treatment of type 2 diabetes, have demonstrated promising neuroprotective effects. This review aims to evaluate the effects and underlying mechanisms of GLP-1 RAs in the context of AD. A comprehensive search of databases yielded 622 articles, from which studies met the predefined inclusion criteria and were subjected to detailed analysis, 29 articles were deemed appropriate for analysis. The results indicate that GLP-1 RAs can significantly reduce amyloid-beta (Aβ) deposition and phosphorylated tau levels in the brains of AD patients. These neuroprotective effects are attributed to multiple synergistic mechanisms, including the enhancement of neuronal survival, reduction of oxidative stress, and attenuation of neuroinflammation. This review underscores the importance of further research to fully elucidate the mechanisms of GLP-1 RAs and their potential as a therapeutic strategy for AD.

Novel Therapeutic Strategies for Alzheimer's Disease

The molecular pathogenesis of Alzheimer's disease (AD) has been elucidated through the biochemical analysis of senile plaques, neurofibrillary tangles, and pathological features of the brains of patients with AD. Genetic analysis, initiated with familial AD investigation, has revealed that Aβ aggregation and accumulation are crucial processes in AD pathogenesis. The success of lecanemab against aggregated Aβ is the result of these efforts. Meanwhile, research on tau as a causative molecule in AD and various other tauopathies is advancing gradually. Furthermore, genetic analysis has revealed that the inflammatory response of glial cells modifies AD pathophysiology; a novel therapeutic strategy for inflammation control is thus currently under consideration. This article summarizes the latest discoveries related to these new therapeutic strategies for AD.

Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a β-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 μM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner

AimsMicroglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. Methods and key findingsTo create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aβ) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aβ plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aβ1–42-induced apoptosis. SignificanceThese findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.

Microglial modulation as a therapeutic strategy in Alzheimer's disease: Focus on microglial preconditioning approaches.

Alzheimer's disease (AD) is a progressive disease that causes an impairment of learning and memory. Despite the highly complex pathogenesis of AD, amyloid beta (Aβ) deposition and neurofibrillary tangles (NFTs) formation are the main hallmarks of AD. Neuroinflammation also has a crucial role in the development of AD. As the central nervous system's innate immune cells, microglial cells are activated in AD and induce inflammation by producing pro-inflammatory mediators. However, microglial activation is not always deleterious. M2-activated microglial cells are considered anti-inflammatory cells, which develop neuroprotection. Various approaches are proposed for managing AD, yet no effective therapy is available for this disorder. Considering the potential protective role of M2 microglia in neurodegenerative disorders and the improvement of these disorders by preconditioning approaches, it can be suggested that preconditioning of microglial cells may be beneficial for managing AD progression. Therefore, this study review microglial preconditioning approaches for preventing and improving AD.

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease.

As a dietary strategy, methionine restriction has been reported to promote longevity and regulate metabolic disorders. However, the role and possible regulatory mechanisms underlying methionine in neurodegenerative diseases such as Alzheimer's disease (AD), remain unexplored. This study utilized the data from BXD recombinant inbred (RI) mice to establish a correlation between the AD phenotype in mice and methionine level. Gene enrichment analysis indicated that the genes associated with the concentration of methionine in the midbrain are involved in the dopaminergic synaptic signaling pathway. Protein interaction network analysis revealed that glycogen synthase kinase 3 beta (GSK-3β) was a key regulator of the dopaminergic synaptic pathway and its expression level was significantly correlated with the AD phenotype. Finally, in vitro experiments demonstrated that methionine deprivation could reduce the expression of Aβ and phosphorylated Tau, suggesting that lowering methionine levels in humans may be a preventive or therapeutic strategy for AD. In conclusion, our findings support that methionine is a high risk factor for AD. These findings predict potential regulatory network, theoretically supporting methionine restriction to prevent AD.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aβ plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Integrated Systems Analysis Deciphers Transcriptome and Glycoproteome Links in Alzheimer's Disease.

Glycosylation is increasingly recognized as a potential therapeutic target in Alzheimer's disease. In recent years, evidence of Alzheimer's disease-specific glycoproteins has been established. However, the mechanisms underlying their dysregulation, including tissue- and cell-type specificity, are not fully understood. We aimed to explore the upstream regulators of aberrant glycosylation by integrating multiple data sources using a glycogenomics approach. We identified dysregulation of the glycosyltransferase PLOD3 in oligodendrocytes as an upstream regulator of cerebral vessels and found that it is involved in COL4A5 synthesis, which is strongly correlated with amyloid fiber formation. Furthermore, COL4A5 has been suggested to interact with astrocytes via extracellular matrix receptors as a ligand. This study suggests directions for new therapeutic strategies for Alzheimer's disease targeting glycosyltransferases.

Novel Therapeutic Strategies in Alzheimer's Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond.

Alzheimer's disease (AD) causes a significant challenge to global healthcare systems, with limited effective treatments available. This review examines the landscape of novel therapeutic strategies for AD, focusing on the shortcomings of traditional therapies against amyloid-beta (Aβ) and exploring emerging alternatives. Despite decades of research emphasizing the role of Aβ accumulation in AD pathogenesis, clinical trials targeting Aβ have obtained disappointing results, highlighting the complexity of AD pathophysiology and the need for investigating other therapeutic approaches. In this manuscript, we first discuss the challenges associated with anti-Aβ therapies, including limited efficacy and potential adverse effects, underscoring the necessity of exploring alternative mechanisms and targets. Thereafter, we review promising non-Aβ-based strategies, such as tau-targeted therapies, neuroinflammation modulation, and gene and stem cell therapy. These approaches offer new avenues for AD treatment by addressing additional pathological hallmarks and downstream effects beyond Aβ deposition.

Gene expression patterns of CRYM and SIGLEC10 in Alzheimer's disease: potential early diagnostic indicators.

Alzheimer's disease (AD) is a neurological condition that may lead to dementia as well as a slow and steady decline in cognitive ability. Finding early signs that may be used in the diagnosis of ADis still a difficult aim to achieve in the field of medical practice. The purpose of this research was to investigate to determineany differences in the gene expression patterns of crystallin mu (CRYM) and sialic acid-binding immunoglobulin-like lectin 10 (SIGLEC10) in whole blood samples obtained from fifty individuals who were diagnosed with ADand fifty individuals as a control group. When compared with controls, it was discovered that the expression of the CRYM gene was substantially decreased in AD patients, but the expression of the SIGLEC10 gene was significantly higher. A positive correlation between CRYM and SIGLEC10 was noticed solely in patients with AD. Furthermore, assessing the diagnostic value of these genes, CRYM and SIGLEC10 transcript levels displayed an area under the curve (AUC) of 0.74 and 0.81, respectively. These results suggest that alterations in CRYM and SIGLEC10 expression may be implicated in AD pathology and that these genes expression levels can potentially serve as biomarkers for early detection and diagnosis of AD. Nevertheless, further validation of these findings requires the inclusion of more extensive and heterogeneous cohorts. The findings derived from this study possess the capability to offer a significant contribution towards the progression of innovative diagnostic and therapeutic strategies for AD.

Modulation of Tau Pathology in Alzheimer's Disease by Dietary Bioactive Compounds.

Tau is a microtubule-associated protein essential for microtubule assembly and stability in neurons. The abnormal intracellular accumulation of tau aggregates is a major characteristic of brains from patients with Alzheimer's disease (AD) and other tauopathies. In AD, the presence of neurofibrillary tangles (NFTs), which is composed of hyperphosphorylated tau protein, is positively correlated with the severity of the cognitive decline. Evidence suggests that the accumulation and aggregation of tau cause synaptic dysfunction and neuronal degeneration. Thus, the prevention of abnormal tau phosphorylation and elimination of tau aggregates have been proposed as therapeutic strategies for AD. However, currently tau-targeting therapies for AD and other tauopathies are limited. A number of dietary bioactive compounds have been found to modulate the posttranslational modifications of tau, including phosphorylation, small ubiquitin-like modifier (SUMO) mediated modification (SUMOylation) and acetylation, as well as inhibit tau aggregation and/or promote tau degradation. The advantages of using these dietary components over synthetic substances in AD prevention and intervention are their safety and accessibility. This review summarizes the mechanisms leading to tau pathology in AD and highlights the effects of bioactive compounds on the hyperphosphorylation, aggregation and clearance of tau protein. The potential of using these bioactive compounds for AD prevention and intervention is also discussed.

Prevention of amyloid β fibril deposition on the synaptic membrane in the precuneus by ganglioside nanocluster-targeting inhibitors.

Alzheimer's disease (AD), a progressive neurodegenerative condition, is one of the most common causes of dementia. Senile plaques, a hallmark of AD, are formed by the accumulation of amyloid β protein (Aβ), which starts to aggregate before the onset of the disease. Gangliosides, sialic acid-containing glycosphingolipids, play a key role in the formation of toxic Aβ aggregates. In membrane rafts, ganglioside-bound complexes (GAβ) act as nuclei for Aβ assembly, suggesting that GAβ is a promising target for AD therapy. The formation of GAβ-induced Aβ assemblies has been evaluated using reconstituted planar lipid membranes composed of synaptosomal plasma membrane (SPM) lipids extracted from human and mouse brains. Although the effects of gangliosides on Aβ accumulation in the precuneus have been established, effects on Aβ fibrils have not been determined. In this study, Aβ42 fibrils on reconstituted membranes composed of SPM lipids prepared from the precuneus cortex of human autopsied brains were evaluated by atomic force microscopy. In particular, Aβ42 accumulation, as well as the fibril number and size were higher for membranes with precuneus lipids than for membranes with calcarine cortex lipids. In addition, artificial peptide inhibitors targeting Aβ-sensitive ganglioside nanoclusters cleared Aβ assemblies on synaptic membranes in the brain, providing a novel therapeutic strategy for AD.

Huanshaodan regulates microglial glucose metabolism reprogramming to alleviate neuroinflammation in AD mice through mTOR/HIF-1α signaling pathway.

Abnormal glucose metabolism in microglial is closely associated with Alzheimer's disease (AD). Reprogramming of microglial glucose metabolism is centered on regulating the way in which microglial metabolize glucose to alter microglial function. Therefore, reprogramming microglial glucose metabolism is considered as a therapeutic strategy for AD. Huanshaodan (HSD) is a Chinese herbal compound which shows significant efficacy in treating AD, however, the precise mechanism by which HSD treats AD remains unclear. This study is aim to investigate whether HSD exerts anti-AD effects by regulating the metabolic reprogramming of microglial through the mTOR/HIF-1α signaling pathway. SAMP8 mice and BV2 cells were used to explore the alleviative effect of HSD on AD and the molecular mechanism in vivo and in vitro. The pharmacodynamic effects of HSD was evaluated by behavioral tests. The pathological deposition of Aβ in brain of mice was detected by immunohistochemistry. ELISA method was used to measure the activity of HK2 and the expression of PKM2, IL-6 and TNF-α in hippocampus and cortex tissues of mice. Meanwhile, proteins levels of p-mTOR, mTOR, HIF-1α, CD86, Arg1 and IL-1β were detected by Western-blot. LPS-induced BV2 cells were treated with HSD-containing serum. The analysis of the expression profiles of the CD86 and CD206 markers by flow cytometry allows us to distinguish the BV2 polarization. Glucose, lactic acid, ATP, IL-6 and TNF-α levels, as well as lactate dehydrogenase and pyruvate dehydrogenase activities were evaluated in the BV2. Western-blot analysis was employed to detect mTOR, p-mTOR, HIF-1α and IL-1β levels in BV2. And the mTOR agonist MHY1485 (MHY) was chosen to reverse validate. In this study, it is found that HSD improved cognitive impairment in SAMP8 mice and reduced Aβ deposition, suppressed the levels of glycolysis and neuroinflammation in mice. In LPS-induced BV2 cells, HSD also regulated glycolysis and neuroinflammation, and suppressed the mTOR/HIF-1α signaling pathway. More importantly, these effects were reversed by MHY. It is demonstrated that HSD regulated microglial glucose metabolism reprogramming by inhibiting the mTOR/HIF-1α signaling pathway, alleviated neuroinflammation, and exerted anti-AD effects. This study provided scientific evidence for the clinical application of HSD for treating AD.

Neuromodulation in Alzheimer’s Disease in the Therapy Process

Increasing prevalence in the near future of Alzheimer’s disease (AD) has been statistically predicted. As current pharmacological treatments turn out to be limited for the long-term clinical effects accompanying various side effects and complications, new schemes are in urgent need of a relatively safer and more effective treatment. In recent years, neuromodulation technologies such as optogenetics, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), transcranial electrical stimulation (tES), deep brain stimulation (DBS), and focused ultrasound (FUS), which are proven with potential remedial effectiveness in several mental diseases, emerge to be a prospective therapeutic strategy for AD. By applying optical, magnetic, as well as electronic technology, modulations on specific brain regions can be achieved. And by applying ultrasonic technology, the process of medical molecules passing through the brain-blood barrier (BBB) can be facilitated. This article summarizes the current knowledge of some main neuromodulation technologies and provides insight into their possibilities for clinical application. By further illuminating the clinical effects, advantages, and limitations of these technologies, the article may help to guide clinical practice and enlighten new ideas for therapeutic strategy in AD.

Novel systemic delivery of a peptide‐mediated anti‐sense oligonucleotide to reduce α‐synuclein in a mouse model of Alzheimer’s Disease

AbstractBackgroundNeurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α‐synuclein (α‐syn) and amyloid beta (Aβ). Misfolded and aggregated α‐syn has been implicated in neurological disorders such as Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer’s Disease (AD). However, accumulation of α‐syn has been confirmed in over 50% of postmortem brains of AD patients. To date, no therapeutic strategy has consistently downregulated α‐syn in AD.MethodHere we tested the hypothesis that using a peptide (ApoB11) that binds a modified antisense oligonucleotide (2’‐O‐methyl si α‐syn or 2’‐OMe) for transport across the blood‐brain barrier following systemic administration, would downregulate α‐syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. We tested the efficacy of the ASO in knocking down α‐syn both in vitro, using neuronal cell lines, and in vivo by measuring α‐syn levels in brains of treated mice with 2mg/kg at 6, 7 and 8 months of age.ResultWe found that treatment of APP transgenic mice with systemic delivery of ApoB11:ASO‐α‐syn reduces expression of α‐synuclein in specific regions of hippocampi of 9 month‐old APP transgenic mice. Downregulation of α‐syn led to a significant reduction of Aβ plaques burden, rescued neuronal loss and prevented astrogliosis, as compared to untreated PSAPP mice. Importantly, we found that AD mice treated with the ASO‐syn had greatly improved hippocampal and spatial memory function as shown by Morris Water Maze tests.ConclusionCollectively, the data shown in this work supports the use of ApoB11:ASO α‐syn conjugates delivered systemically to downregulate α‐syn as a promising future therapeutic strategy in AD. Our work suggests that knocking down α‐syn could be necessary to prevent neuropathology and prevent spatial memory loss.