Potential Therapy For Alzheimer's Disease Research Articles

Alzheimer's disease drug development pipeline: 2024

New therapies to prevent or delay the onset of symptoms, slow progression, or improve cognitive and behavioral symptoms of Alzheimer's disease (AD) are needed. We interrogated clinicaltrials.gov including all clinical trials assessing pharmaceutical therapies for AD active in on January 1, 2024. We used the Common Alzheimer's Disease Research Ontology (CADRO) to classify the targets of therapies in the pipeline. There are 164 trials assessing 127 drugs across the 2024 AD pipeline. There were 48 trials in Phase 3 testing 32 drugs, 90 trials in Phase 2 assessing 81 drugs, and 26 trials in Phase 1 testing 25 agents. Of the 164 trials, 34% (N = 56) assess disease-modifying biological agents, 41% (N = 68) test disease-modifying small molecule drugs, 10% (N = 17) evaluate cognitive enhancing agents, and 14% (N = 23) test drugs for the treatment of neuropsychiatric symptoms. Compared to the 2023 pipeline, there are fewer trials (164vs. 187), fewer drugs (127vs. 141), fewer new chemical entities (88vs. 101), and a similar number of repurposed agents (39vs. 40). In the 2024 Alzheimer's disease drug development pipeline, there are 164 clinical trials assessing 127 drugs.The 2024 Alzheimer's disease drug development pipeline has contracted compared to the 2023 Alzheimer pipeline with fewer trials, fewer drugs, and fewer new chemical entities.Drugs in the Alzheimer's disease drug development pipeline target a wide array of targets; the most common processes targeted include neurotransmitter receptors, inflammation, amyloid, and synaptic plasticity.The total development time for a potential Alzheimer's disease therapy to progress from nonclinical studies to FDA review is approximately 13 years.

Blockade of adenosine A2A receptors reverses early spatial memory defects in the APP/PS1 mouse model of Alzheimer’s disease by promoting synaptic plasticity of adult-born granule cells

BackgroundThe over-activation of adenosine A2A receptors (A2AR) is closely implicated in cognitive impairments of Alzheimer's disease (AD). Growing evidence shows that A2AR blockade possesses neuroprotective effects on AD. Spatial navigation impairment is an early manifestation of cognitive deficits in AD. However, whether A2AR blockade can prevent early impairments in spatial cognitive function and the underlying mechanism is still unclear.MethodsA transgenic APP/PS1 mouse model of AD amyloidosis was used in this study. Behavioral tests were conducted to observe the protective effects of A2AR blockade on early spatial memory deficits in 4-month old APP/PS1 mice. To investigate the underlying synaptic mechanism of the protective effects of A2AR blockade, we further examined long-term potentiation (LTP) and network excitation/inhibition balance of dentate gyrus (DG) region, which is relevant to unique synaptic functions of immature adult-born granule cells (abGCs). Subsequently, the protective effects of A2AR blockade on dendritic morphology and synaptic plasticity of 6-week-old abGCs was investigated using retrovirus infection and electrophysiological recordings. The molecular mechanisms underlying neuroprotective properties of A2AR blockade on the synaptic plasticity of abGCs were further explored using molecular biology methods.ResultsAPP/PS1 mice displayed DG-dependent spatial memory deficits at an early stage. Additionally, impaired LTP and an imbalance in network excitation/inhibition were observed in the DG region of APP/PS1 mice, indicating synaptic structural and functional abnormalities of abGCs. A2AR was found to be upregulated in the hippocampus of the APP/PS1 mouse model of AD. Treatment with the selective A2AR antagonist SCH58261 for three weeks significantly ameliorated spatial memory deficits in APP/PS1 mice and markedly restored LTP and network excitation/inhibition balance in the DG region. Moreover, SCH58261 treatment restored dendritic morphology complexity and enhanced synaptic plasticity of abGCs in APP/PS1 mice. Furthermore, SCH58261 treatment alleviated the impairment of synaptic plasticity in abGCs. It achieved this by remodeling the subunit composition of NMDA receptors and increasing the proportion of NR2B receptors in abGCs of APP/PS1 mice.ConclusionsBlockade of A2AR improves early spatial memory deficits in APP/PS1 mice, possibly by reversing synaptic defects of abGCs. This finding suggests that A2AR blockade could be a potential therapy for AD.

Unveiling the Potential of Polyphenols as Anti-Amyloid Molecules in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that mostly affects the elderly population. Mechanisms underlying AD pathogenesis are yet to be fully revealed, but there are several hypotheses regarding AD. Even though free radicals and inflammation are likely to be linked with AD pathogenesis, still amyloid-beta (Aβ) cascade is the dominant hypothesis. According to the Aβ hypothesis, a progressive buildup of extracellular and intracellular Aβ aggregates has a significant contribution to the AD-linked neurodegeneration process. Since Aβ plays an important role in the etiology of AD, therefore Aβ-linked pathways are mainly targeted in order to develop potential AD therapies. Accumulation of Aβ plaques in the brains of AD individuals is an important hallmark of AD. These plaques are mainly composed of Aβ (a peptide of 39-42 amino acids) aggregates produced via the proteolytic cleavage of the amyloid precursor protein. Numerous studies have demonstrated that various polyphenols (PPHs), including cyanidins, anthocyanins, curcumin, catechins and their gallate esters were found to markedly suppress Aβ aggregation and prevent the formation of Aβ oligomers and toxicity, which is further suggesting that these PPHs might be regarded as effective therapeutic agents for the AD treatment. This review summarizes the roles of Aβ in AD pathogenesis, the Aβ aggregation pathway, types of PPHs, and distribution of PPHs in dietary sources. Furthermore, we have predominantly focused on the potential of food-derived PPHs as putative anti-amyloid drugs.

Effect of sodium channels in Alzheimer’s disease

Alzheimer disease (AD), depicted by the formation of amyloid β-protein plaque(Aβ), has been recognized for dementia and epilepsy. The pathological mechanism of AD is complicated and it remains unclear. Currently, most therapies are focusing on elimination of Aβ plaque and preventing the breakdown of acetylcholine to prevent neuron cell death, however, most of these drugs fail to improve cognitive functions in AD patients. Therefore, the development of novel therapies for AD is in urgent need. Emerging evidences show that cellular sodium (Na+) signals play a significant role in neurol physiology. Aβ oligomer upregulates the expression of Nav1.6, leading to cognition loss, epilepsy, and malfunction of neuron development (shorter neurite length is observed during Aβ-interfered neuron development), indicating that sodium channel may be a target for treating AD. This review summarizes current development of molecular mechanisms linking sodium dysregulation with AD pathologies and discusses potential therapies for AD by correcting Na+ disruption.

The microglial immunoreceptor tyrosine-based motif-Syk signaling pathway is a promising target of immunotherapy for Alzheimer's disease.

The microglial immunoreceptor tyrosine-based motif-Syk signaling pathway is a promising target of immunotherapy for Alzheimer's disease.

Improving generalizability and study design of Alzheimer's disease cohort studies in the United States by including under-represented populations.

The poor generalizability of clinical research data due to the enrollment of highly educated, non-Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health-care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under-represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally-informed digital research methods, community-engaged research strategies, leadership from under-represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under-represented populations into US-based clinical studies, thereby increasing the generalizability of their results.

Curcumin-Loaded Mesoporous Silica Nanoparticles Dispersed in Thermo-Responsive Hydrogel as Potential Alzheimer Disease Therapy

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 μg cm−2 of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD.

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aβ) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE-Aβ interaction inhibitors produced positive results in transgenic AD mouse models.

Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer's disease.

We previously demonstrated that ibrutinib modulates LPS‐induced neuroinflammation in vitro and in vivo, but its effects on the pathology of Alzheimer's disease (AD) and cognitive function have not been investigated. Here, we investigated the effects of ibrutinib in two mouse models of AD. In 5xFAD mice, ibrutinib injection significantly reduced Aβ plaque levels by promoting the non‐amyloidogenic pathway of APP cleavage, decreased Aβ‐induced neuroinflammatory responses, and significantly downregulated phosphorylation of tau by reducing levels of phosphorylated cyclin‐dependent kinase‐5 (p‐CDK5). Importantly, tau‐mediated neuroinflammation and tau phosphorylation were also alleviated by ibrutinib injection in PS19 mice. In 5xFAD mice, ibrutinib improved long‐term memory and dendritic spine number, whereas in PS19 mice, ibrutinib did not alter short‐ and long‐term memory but promoted dendritic spinogenesis. Interestingly, the induction of dendritic spinogenesis by ibrutinib was dependent on the phosphorylation of phosphoinositide 3‐kinase (PI3K). Overall, our results suggest that ibrutinib modulates AD‐associated pathology and cognitive function and may be a potential therapy for AD.

Selective linkage of mitochondrial enzymes to intracellular calcium stores differs between human-induced pluripotent stem cells, neural stem cells, and neurons.

Mitochondria and releasable endoplasmic reticulum (ER) calcium modulate neuronal calcium signaling, and both change in Alzheimer's disease (AD). The releasable calcium stores in the ER are exaggerated in fibroblasts from AD patients and in multiple models of AD. The activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key mitochondrial enzyme complex, is diminished in brains from AD patients, and can be plausibly linked to plaques and tangles. Our previous studies in cell lines and mouse neurons demonstrate that reductions in KGDHC increase the ER releasable calcium stores. The goal of these studies was to test whether the relationship was true in human iPSC-derived neurons. Inhibition of KGDHC for one or 24hr increased the ER releasable calcium store in human neurons by 69% and 144%, respectively. The effect was mitochondrial enzyme specific because inhibiting the pyruvate dehydrogenase complex, another key mitochondrial enzyme complex, diminished the ER releasable calcium stores. The link of KGDHC to ER releasable calcium stores was cell type specific as the interaction was not present in iPSC or neural stem cells. Thus, these studies in human neurons verify a link between KGDHC and releasable ER calcium stores, and support the use of human neurons to examine mechanisms and potential therapies for AD.

Riluzole ameliorates soluble Aβ1–42-induced impairments in spatial memory by modulating the glutamatergic/GABAergic balance in the dentate gyrus

Soluble amyloid beta (Aβ) is believed to contribute to cognitive deficits in the early stages of Alzheimer's disease (AD). Increased soluble Aβ1–42 in the hippocampus is closely correlated with spatial learning and memory deficits in AD. Riluzole (RLZ), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), has beneficial effects for AD. However, the mechanism underlying the effects remains unclear. In this study, its neuroprotective effect against soluble Aβ1–42-induced spatial cognitive deficits in rats was assessed. We found that intrahippocampal injection of soluble Aβ1–42 impaired spatial cognitive function and suppressed long-term potentiation (LTP) of the DG region, which was relevant to soluble Aβ1–42-induced shift of the hippocampal excitation/inhibition balance toward excitation. Interestingly, RLZ ameliorated Aβ1–42-induced behavioral and LTP impairments through rescuing the soluble Aβ1–42-induced excitation/inhibition imbalance. RLZ attenuated Aβ1–42-mediated facilitation of excitatory synaptic transmission by facilitating glutamate reuptake and decreasing presynaptic glutamate release. Meanwhile, RLZ attenuated the suppression of inhibitory synaptic transmission caused by Aβ1–42 by potentiating postsynaptic GABA receptor function. These results suggest that RLZ exerts a neuroprotective effect against soluble Aβ1–42-related spatial cognitive deficits through rescuing the excitation/inhibition imbalance, and it could be a potential therapy for AD.

Circular Dichroism Spectroscopy Identifies the β-Adrenoceptor Agonist Salbutamol As a Direct Inhibitor of Tau Filament Formation in Vitro.

Potential drug treatments for Alzheimer's disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilization and cell death. Here, a small library of structurally diverse compounds was screened in vitro for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 screened compounds. Subsequently, we tested chemically similar phenolamine drugs from the β-adrenergic receptor agonist class, using conventional circular dichroism spectroscopy, thioflavin T fluorescence, and transmission electron microscopy. Two compounds, salbutamol and dobutamine, used widely in the treatment of respiratory and cardiovascular disease, impede the aggregation of tau in vitro. Dobutamine reduces both the rate and yield of tau filament formation over 24 h; however, it has little effect on the structural transition of tau into β-sheet structures over 24 h. Salbutamol also reduces the yield and rate of filament formation and additionally inhibits tau's structural change into β-sheet-rich aggregates. Salbutamol has a good safety profile and a half-life that facilitates permeation through the blood-brain barrier and could represent an expediated approach to developing AD therapeutics. These results provide the motivation for the in vivo evaluation of pre-existing β-adrenergic receptor agonists as a potential therapy for AD through the reduction of tau deposition.

Trehalose against Alzheimer's Disease: Insights into a Potential Therapy.

Trehalose is a natural disaccharide with a remarkable ability to stabilize biomolecules. In recent years, trehalose has received growing attention as a neuroprotective molecule and has been tested in experimental models for different neurodegenerative diseases. Although the underlying neuroprotective mechanism of trehalose's action is unclear, one of the most important hypotheses is autophagy induction. The chaperone-like activity of trehalose and the ability to modulate inflammatory responses has also been reported. There is compelling evidence that the dysfunction of autophagy and aggregation of misfolded proteins contribute to the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Therefore, given the linking between trehalose and autophagy induction, it appears to be a promising therapy for AD. Herein, the published studies concerning the use of trehalose as a potential therapy for AD are summarized, providing a rationale for applying trehalose to reduce Alzheimer's pathology.

The NLRP3 inflammasome as a bridge between neuro-inflammation in metabolic and neurodegenerative diseases.

Evidence increasingly suggests that type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases share many pathological processes, including oxidative stress, local inflammation/neuroinflammation and chronic, low-grade (systemic) inflammation, which are exacerbated by aging, a common risk factor for T2DM and NDDs. Here, we focus on the link between chronic inflammation driven by peripheral metabolic disease and how this may impact neurodegeneration in AD and PD. We review the relationship between these common pathological processes in AD and PD from the perspective of the "pro-inflammatory" signaling of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex. Since the need for effective disease-modifying therapies in T2DM, AD and PD is significant, the relationship between these diseases is important as a positive clinical impact on one may benefit the others. We briefly consider how novel strategies may target neuro-inflammation and provide potential therapies for AD and PD.

Lanosterol Disrupts the Aggregation of Amyloid-β Peptides.

Lanosterol, an amphipathic molecule, was discovered only very recently to effectively hinder the aggregation of lens proteins and dissolve the extremely stable fibrillar aggregates in cataracts. Here, we combined computational and experimental approaches to study how lanosterol disrupts the aggregation of another important peptide, amyloid-β (Aβ) peptide, associated with the Alzheimer's Disease (AD). Molecular dynamics simulations using the core amyloidogenic segment (KLVFFA) of Aβ peptide revealed that lanosterol exhibits at least two types of inhibition mechanism on the self-assembly of Aβ peptides. First, lanosterol entangles with peptides and forms a hydrophobic core with residues Phe-19 and Phe-20 in particular. Second, it interferes with the steric zipper interaction at the β-sheet-β-sheet interface. These simulation data suggest that lanosterol induces the unfolding of the Aβ peptide and the separation of the β-sheet layers. This predicted inhibition effect of lanosterol was then confirmed by an in vitro ThT fluorescence assay and AFM imaging. The cell toxicity assay also showed that the treatment of lanosterol indeed mitigates the cytotoxicity of the Aβ peptide in PC-12 cells. Moreover, lanosterol shows a stronger suppression effect on Aβ peptides' aggregation than cholesterol because of its higher hydrophobicity. This result establishes a foundation for the development of lanosterol-based potential therapies for AD and other protein conformational diseases.

Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease.

Calcium (Ca2+) hypothesis of Alzheimer's disease (AD) gains popularity. It points to new signaling pathways that may underlie AD pathogenesis. Based on calcium hypothesis, novel targets for the development of potential AD therapies are identified. Recent Advances: Recently, the key role of neuronal store-operated calcium entry (nSOCE) in the development of AD has been described. Correct regulation of nSOCE is necessary for the stability of postsynaptic contacts to preserve the memory formation. Molecular identity of hippocampal nSOCE is defined. Perspective nSOCE-activating molecule, prototype of future anti-AD drugs, is described. Endoplasmic reticulum Ca2+ overload happens in many but not in all AD models. The nSOCE targeting therapy described in this review may not be universally applicable. There is a need to determine whether AD is a syndrome with one critical signaling pathway that initiates pathology, or it is a disorder with many different signaling pathways that are disrupted simultaneously or one after each other. It is necessary to validate applicability of nSOCE-activating therapy for the development of anti-AD medication. There is an experimental correlation between downregulated nSOCE and disrupted postsynaptic contacts in AD mouse models. Signaling mechanisms downstream of nSOCE which are responsible for the regulation of stability of postsynaptic contacts have to be discovered. That will bring new targets for the development of AD-preventing therapies. Antioxid. Redox Signal. 29, 1176-1188.

NBD-BPEA regulates Zn2+- or Cu2+-induced Aβ40 aggregation and cytotoxicity

Abnormal interaction of amyloid-β peptide (Aβ) and metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Using metal chelators to reverse metal-triggered Aβ aggregation has become one of the potential therapies for AD. In our work, the effect of metal chelator, NBD-BPEA, on Zn2+- or Cu2+-mediated Aβ40 aggregation and neurotoxicity has been systematically studied. NBD-BPEA exhibits the capability to inhibit the metal-mediated Aβ40 aggregation and disassemble performed Aβ40 aggregates. It also prevents the formation of the β-sheet structure and promotes the reversion of the β-sheet to the normal random coil conformation. Moreover, it can alleviate Zn2+- or Cu2+-Aβ40-induced neurotoxicity, suppress the intracellular ROS and protect against cell apoptosis. These preliminary findings indicate that NBD-BPEA has promising perspective of application in the treatment of AD, and therefore deserve further investigation as potential anti-AD agents.

Oxygen Supplementation Improves Protein Milieu Supportive of Protein Synthesis and Antioxidant Function in the Cortex of Alzheimer's Disease Model Mice-a Quantitative Proteomic Study.

Protein synthesis has been reported to be impaired in early-stage Alzheimer's disease (AD). Previously, we found that oxygen supplementation improved cognitive function and reduced mitochondrial damage in AD model mice. In the present study, we examined the effects of supplemental oxygen treatment on protein synthesis and oxidative damage. The synthesis of numerous proteins involved in mRNA splicing, transcription regulation, and translation was found to be significantly upregulated in cortex tissues of AD model mice given a supplemental oxygen treatment (OT group), relative to those of non-treated control AD model mice (Ctrl group), suggesting that impairment in protein synthesis may be alleviated by increased oxygen inhalation. Methionine oxidation and oxidation levels in general were similar between the OT and Ctrl groups, indicating that the oxygen supplementation treatment did not cause increases in peptide oxidation levels. On the contrary, the OT group exhibited upregulation of several proteins associated with antioxidant defense. These results support further exploration into the development of supplementary oxygen treatment as a potential therapy for AD.

Alzheimer's disease and cytokine IL-10 gene polymorphisms: is there an association?

Alzheimer's disease (AD) is the most common form of dementia. In the last 15 years, a new theory has proposed the autoimmune mechanism as a trigger for AD. Studies on the association between AD and inflammatory biomarkers have yielded controversial results. Interleukin-10 (IL-10), an anti-inflammatory mediator, has been pointed out as one of the main cytokines associated with the occurrence of AD. Moreover, treatment that increases IL-10 levels could be a potential therapy for AD, since this cytokine acts on amyloid and pro-inflammatory molecule reduction. Based on the current literature, this study reviews evidence regarding the role of IL-10 polymorphisms in the context of AD, which has been shown to be of paramount importance for attenuating neuroinflammation, cognitive dysfunction and neurodegeneration.

PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β.

Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD.