Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification.

INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. HIGHLIGHTS: We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.

Asymmetric Total Syntheses of Rhynchophylline and Isorhynchophylline.

The asymmetric total syntheses of (-)-rhynchophylline and (+)-isorhynchophylline were achieved in 17 and 16 steps, respectively, from butanal and ethyl acrylate. Our synthesis features Carreira ring expansion to construct the tetracyclic spirooxindole core in high diastereoselectivity and the use of Bosch's chiral lactam for preparation of enantioenriched cyclic imine.

Two pairs of unusual melibiose and raffinose esters from Scrophularia ningpoensis.

A pair of unusual melibiose esters (1α/1ß) and a pair of unusual raffinose esters (2α/2ß), were isolated from Scrophularia ningpoensis. Structures of them were established by detailed spectroscopic analyses to be 6-O-(E)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α(ß)-d-glucopyranose (1α/1ß) and 6-O-(E)/(Z)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α-d-glucopyranosyl-(1→2)-ß-d-fructofuranose (2α/2ß), respectively. All these compounds were evaluated for antifouling activity against the settlement of Balanus amphitrite larvae, along with the cytotoxic effect against the proliferation of HeLa cell lines.

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease.

Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-ß oligomers (Aß), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.

Coronin 6 regulates acetylcholine receptor clustering through modulating receptor anchorage to actin cytoskeleton.

The maintenance of a high density of neurotransmitter receptors at the postsynaptic apparatus is critical for efficient neurotransmission. Acetylcholine receptors (AChRs) are neurotransmitter receptors densely packed on the postsynaptic muscle membrane at the neuromuscular junction (NMJ) via anchoring onto the actin cytoskeletal network. However, how the receptor-associated actin is coordinately regulated is not fully understood. We report here that Coronin 6, a newly identified member of the coronin family, is highly enriched at adult NMJs and regulates AChR clustering through modulating the interaction between receptors and the actin cytoskeletal network. Experiments with cultured myotubes reveal that Coronin 6 is important for both agrin- and laminin-induced AChR clustering. Furthermore, Coronin 6 forms a complex with AChRs and actin in a manner dependent on its C-terminal region and a conserved Arg(29) residue at the N terminus, both of which are critical for the cytoskeletal anchorage of AChRs. Importantly, in vivo knockdown of Coronin 6 in mouse skeletal muscle fibers leads to destabilization of AChR clusters. Together, these findings demonstrate that Coronin 6 is a critical regulator of AChR clustering at the postsynaptic region of the NMJs through modulating the receptor-anchored actin cytoskeleton.

Highly trans-selective arylation of Achmatowicz rearrangement products by reductive γ-deoxygenation and Heck-Matsuda reaction: asymmetric total synthesis of (-)-musellarins†A-C and their analogues.

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji-Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck-Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads.

Cycloastragenol is a potent telomerase activator in neuronal cells: implications for depression management.

Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression-like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression.

Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors.

Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS,S)-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC(50) value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM.

Deep learning-based polygenic risk analysis for Alzheimer's disease prediction.

BACKGROUND: The polygenic nature of Alzheimer's disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual's genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Because of the complexity of genomic data, current statistical analyses cannot comprehensively capture the polygenic risk of AD, resulting in unsatisfactory disease risk prediction. However, deep learning methods, which capture nonlinearity within high-dimensional genomic data, may enable more accurate disease risk prediction and improve our understanding of AD etiology. Accordingly, we developed deep learning neural network models for modeling AD polygenic risk. METHODS: We constructed neural network models to model AD polygenic risk and compared them with the widely used weighted polygenic risk score and lasso models. We conducted robust linear regression analysis to investigate the relationship between the AD polygenic risk derived from deep learning methods and AD endophenotypes (i.e., plasma biomarkers and individual cognitive performance). We stratified individuals by applying unsupervised clustering to the outputs from the hidden layers of the neural network model. RESULTS: The deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms. CONCLUSION: Our results suggest that deep learning methods are effective for modeling the genetic risks of AD and other diseases, classifying disease risks, and uncovering disease mechanisms.

Polygenic diseases, such as Alzheimer's disease (AD), are those caused by the interplay between multiple genetic risk factors. Statistical models can be used to predict disease risk based on a person's genetic profile. However, there are limitations to existing methods, while emerging methods such as deep learning may improve risk prediction. Deep learning involves computer-based software learning from patterns in data to perform a certain task, e.g. predict disease risk. Here, we test whether deep learning models can help to predict AD risk. Our models not only outperformed existing methods in modeling AD risk, they also allow us to estimate an individual's risk of AD and determine the biological processes that may be involved in AD. With further testing and optimization, deep learning may be a useful tool to help accurately predict risk of AD and other diseases.

Astragaloside IV and cycloastragenol stimulate the phosphorylation of extracellular signal-regulated protein kinase in multiple cell types.

Two Chinese herb-derived small molecule telomerase activators, astragaloside IV (AG-IV) and cycloastragenol (CAG), have recently been shown to improve the proliferative response of CD8+ T lymphocytes from HIV-infected patients by upregulating telomerase activity. Here, we examined the signaling mechanism of AG-IV and CAG. Telomerase activity in human embryonic kidney HEK293 fibroblasts was increased upon treatment with increasing concentrations of AG-IV or CAG. Both compounds induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) in a time- and dose-dependent manner in HEK293 cells and HEK-neo keratinocytes. AG-IV and CAG also stimulated ERK phosphorylation in other cell lines of lung, brain, mammary, endothelial, and hematopoietic origins. Use of selective inhibitors and dominant negative mutants revealed the involvement of c-Src, MEK (ERK kinase), and epidermal growth factor receptor in CAG-induced ERK phosphorylation. Our data indicate that AG-IV and CAG may exert their cellular effects through the activation of the Src/MEK/ERK pathway.

Demographics and Medication Use of Patients with Late-Onset Alzheimer's Disease in Hong Kong.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. OBJECTIVE: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. METHODS: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care of the Hospital Authority between January 1, 2007 and December 31, 2017. RESULTS: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for > 1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. CONCLUSION: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases.

Association of SPI1 Haplotypes with Altered SPI1 Gene Expression and Alzheimer's Disease Risk.

BACKGROUND: Genetic studies reveal that single-nucleotide polymorphisms (SNPs) of SPI1 are associated with Alzheimer's disease (AD), while their effects in the Chinese population remain unclear. OBJECTIVE: We aimed to examine the AD-association of SPI1 SNPs in the Chinese population and investigate the underlying mechanisms of these SNPs in modulating AD risk. METHODS: We conducted a genetic analysis of three SPI1 SNPs (i.e., rs1057233, rs3740688, and rs78245530) in a Chinese cohort (n = 333 patients with AD, n = 721 normal controls). We also probed public European-descent AD cohorts and gene expression datasets to investigate the putative functions of those SNPs. RESULTS: We showed that SPI1 SNP rs3740688 is significantly associated with AD in the Chinese population (odds ratio [OR] = 0.72 [0.58-0.89]) and identified AD-protective SPI1 haplotypes ß (tagged by rs1057233 and rs3740688) and γ (tagged by rs3740688 and rs78245530). Specifically, haplotypes ß and γ are associated with decreased SPI1 gene expression level in the blood and brain tissues, respectively. The regulatory roles of these haplotypes are potentially mediated by changes in miRNA binding and the epigenetic landscape. Our results suggest that the AD-protective SPI1 haplotypes regulate pathways involved in immune and neuronal functions. CONCLUSION: This study is the first to report a significant association of SPI1 with AD in the Chinese population. It also identifies SPI1 haplotypes that are associated with SPI1 gene expression and decreased AD risk.

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease.

Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aß) pathology through the modulation of microglial activation and Aß clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer's disease.

One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-beta (Abeta) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of Abeta is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of Abeta in AD pathophysiology are not completely understood. Here, we report the involvement of the transcription factor signal transducer and activator of transcription 3 (STAT3) in mediating Abeta-induced neuronal death. We find that tyrosine phosphorylation of STAT3 is elevated in the cortex and hippocampus of APP/PS1 transgenic mice. Treatment of cultured rat neurons with Abeta or intrahippocampal injection of mice with Abeta both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates Abeta-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after Abeta exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as Abeta-induced activation of STAT3 and caspase-3-dependent neuronal death can be inhibited in tyk2(-/-) neurons. Finally, increased tyrosine phosphorylation of STAT3 is also observed in postmortem brains of AD patients. Our observations collectively reveal a novel role of STAT3 in Abeta-induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology.

Intestinal transport of bis(12)-hupyridone in Caco-2 cells and its improved permeability by the surfactant Brij-35.

The objective of the present study was to elucidate the mechanisms of intestinal transport of bis(12)-hupyridone (B12H) to predict its oral bioavailability. The effect of the B12H concentration and the contribution of the drug efflux transporters, P-glycoprotein (P-gp or ABCB1) and multidrug resistance-associated proteins (MRPs or ABCC) on B12H absorption were measured and evaluated using the human intestinal epithelial Caco-2 cell monolayer in the presence of transporter inhibitors. The results indicated that B12H was absorbed in a dose-dependent manner at concentrations ranging from 132 to 264 µM. However, only apical efflux was observed in the directional transport studies for B12H below 88 µM (P(app) (AP-to-BL): virtually zero; P(app) (BL-to-AP): 1.591 ± 0.071 × 10(-5) cm s(-1) ). P-gp and mixed P-gp/MRP inhibitors significantly increased the absorptive transport (P(app) (AP-to-BL)) to 0.619 ± 0.018 × 10(-5) and 0.608 ± 0.025 × 10(-5) cm s(-1) , respectively, while decreasing secretory transport (P(app) (BL-to-AP)) by >75%. A multiple-MRP inhibitor, probenecid, increased the P(app) (AP-to-BL) to 0.329 ± 0.015 × 10(-5) cm s(-1) while decreasing the P(app) (BL-to-AP) by 50%. Another multiple-MRP inhibitor, indomethacin, only modestly decreased the P(app) (BL-to-AP) by ∼30% and had no effect on the absorptive transport (P(app) (AP-to-BL): virtually zero). In addition, the effect of various pharmaceutical excipients (e.g. Pluronic F-68, Tween-80 and Brij-35) on B12H transport was determined and compared. Among them, Brij-35 effectively enhanced B12H absorption at a concentration lower than its critical micelle concentration (CMC, 60 µM). Therefore, Brij-35 can be used as a potential enhancer to improve intestinal absorption of B12H for oral administration.

Rhynchophylline Administration Ameliorates Amyloid-ß Pathology and Inflammation in an Alzheimer's Disease Transgenic Mouse Model.

Alzheimer's disease (AD), the most common neurodegenerative disease, has limited treatment options. As such, extensive studies have been conducted to identify novel therapeutic approaches. We previously reported that rhynchophylline (Rhy), a small molecule EphA4 inhibitor, rescues impaired hippocampal synaptic plasticity and cognitive dysfunctions in APP/PS1 mice, an AD transgenic mouse model. To assess whether Rhy can be developed as an alternative treatment for AD, it is important to examine its pharmacokinetics and effects on other disease-associated pathologies. Here, we show that Rhy ameliorates amyloid plaque burden and reduces inflammation in APP/PS1 mice. Transcriptome analysis revealed that Rhy regulates various molecular pathways in APP/PS1 mouse brains associated with amyloid metabolism and inflammation, specifically the ubiquitin proteasome system, angiogenesis, and microglial functional states. These results show that Rhy, which is blood-brain barrier permeable, is beneficial to amyloid pathology and regulates multiple molecular pathways.

A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice.

Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC50 < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration.

Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem.

Members of the X11/Mint family of multidomain adaptor proteins are composed of a divergent N terminus, a conserved PTB domain and a pair of C-terminal PDZ domains. Many proteins can interact with the PDZ tandem of X11 proteins, although the mechanism of such interactions is unclear. Here we show that the highly conserved C-terminal tail of X11alpha folds back and inserts into the target-binding groove of the first PDZ domain. The binding of this tail occludes the binding of other target peptides. This autoinhibited conformation of X11 requires that the two PDZ domains and the entire C-terminal tail be covalently connected to form an integral structural unit. The autoinhibited conformation of the X11 PDZ tandem provides a mechanistic explanation for the unique target-binding properties of the protein and hints at potential regulatory mechanisms for the X11-target interactions.

New secoiridoid glucosides from Ligustrum lucidum induce ERK and CREB phosphorylation in cultured cortical neurons.

Two new secoiridoid glucosides, namely iso-oleonuezhenide (1) and methyloleoside 7-ethyl ester (2), along with five known ones, oleonuezhenide (3), nuezhenide (4), oleuropein (5), G13 (6), and jaspolyside methyl ester (7), were isolated from the fruits of Ligustrum lucidum. Their structures were assigned based on 1H-NMR, 13C-NMR, and 2D-NMR analyses, in combination with HR-MS experiments and the comparison with literature data of related compounds, as well as on chemical experiments. We have examined the ability of these compounds to activate ERK and CREB in cultured cortical neurons. Our studies demonstrate that compound 1 induces ERK and CREB phosphorylation in primary cortical neurons in a dose- and temporal-dependent manner, suggesting its bioactivity on neurons.

A Pentacyclic Triterpene from Ligustrum lucidum Targets γ-Secretase.

Amyloid-beta peptides generated by ß-secretase- and γ-secretase-mediated successive cleavage of amyloid precursor protein are believed to play a causative role in Alzheimer's disease. Thus, reducing amyloid-beta generation by modulating γ-secretase remains a promising approach for Alzheimer's disease therapeutic development. Here, we screened fruit extracts of Ligustrum lucidum Ait. (Oleaceae) and identified active fractions that increase the C-terminal fragment of amyloid precursor protein and reduce amyloid-beta production in a neuronal cell line. These fractions contain a mixture of two isomeric pentacyclic triterpene natural products, 3-O-cis- or 3-O-trans-p-coumaroyl maslinic acid (OCMA), in different ratios. We further demonstrated that trans-OCMA specifically inhibits γ-secretase and decreases amyloid-beta levels without influencing cleavage of Notch. By using photoactivatable probes targeting the subsites residing in the γ-secretase active site, we demonstrated that trans-OCMA selectively affects the S1 subsite of the active site in this protease. Treatment of Alzheimer's disease transgenic model mice with trans-OCMA or an analogous carbamate derivative of a related pentacyclic triterpene natural product, oleanolic acid, rescued the impairment of synaptic plasticity. This work indicates that the naturally occurring compound trans-OCMA and its analogues could become a promising class of small molecules for Alzheimer's disease treatment.