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Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.

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Background: Mutations in the presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) genes have been commonly identified in early-onset Alzheimer's disease (EOAD). Some of the mutations in the three causative genes, especially the PSEN1 gene, result in variable phenotypes and exhibit clinical heterogeneity among EOAD families. Methods: Using next-generation sequencing (NGS), we performed genetic screening in a Chinese cohort of 18 patients with EOAD, consisting of five familial EOAD and 13 sporadic cases. Results: We identified two likely pathogenic PSEN1 mutations (one novel) and a novel APP mutation in three cases of EOAD, where two are familial and one is sporadic, respectively. In addition, we detected a few variants of uncertain significance (VUS) in several genes, including not only the two known variants in PSEN2 (p.H169N and p.V214L) but also genes causal of other types of dementia or previously identified as risk factors for AD, suggesting the possible involvement of multiple genes in the etiopathology of AD. The patients carrying PSEN1 mutations had an earlier mean age at the onset than those with PSEN2 or APP variants. The initial symptoms varied greatly among patients in the EOAD cohort, from progressive memory impairment and epilepsy to uncommon motor symptoms such as involuntary tremors in the upper extremities. Conclusions: In conclusion, our study provides further evidence of the genetic profile of patients with EOAD from China and expands the mutation spectrum of both PSEN1 and APP. In addition, our results highlight the clinical heterogeneity in patients with EOAD and mutations in PSEN1, PSEN2, and APP and suggest strong effects of genetic variants on clinical phenotypes. Future functional studies are needed to clarify the interaction between AD-causative gene mutations and phenotypic heterogeneity.

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PURPOSE: Early-onset Alzheimer disease (EOAD) is rare, highly heterogeneous, and associated with poor prognosis. This AT(N) Framework-based study aimed to compare multiprobe PET/MRI findings between EOAD and late-onset Alzheimer disease (LOAD) patients and explore potential imaging biomarkers for characterizing EOAD. METHODS: Patients with AD who underwent PET/MRI in our PET center were retrospectively reviewed and grouped according to the age at disease onset: EOAD, younger than 60 years; and LOAD, 60 years or older. Clinical characteristics were recorded. All study patients had positive ß-amyloid PET imaging; some patients also underwent 18 F-FDG and 18 F-florzolotau PET. Imaging of the EOAD and LOAD groups was compared using region-of-interest and voxel-based analysis. Correlation of onset age and regional SUV ratios were also evaluated. RESULTS: One hundred thirty-three patients were analyzed (75 EOAD and 58 LOAD patients). Sex ( P = 0.515) and education ( P = 0.412) did not significantly differ between groups. Mini-Mental State Examination score was significantly lower in the EOAD group (14.32 ± 6.74 vs 18.67 ± 7.20, P = 0.004). ß-Amyloid deposition did not significantly differ between groups. Glucose metabolism in the frontal, parietal, precuneus, temporal, occipital lobe, and supramarginal and angular gyri was significantly lower in the EOAD group (n = 49) than in the LOAD group (n = 44). In voxel-based morphometry analysis, right posterior cingulate/precuneus atrophy was more obvious in the EOAD ( P < 0.001), although no voxel survived family-wise error correction. Tau deposition in the precuneus, parietal lobe, and angular, supramarginal, and right middle frontal gyri was significantly higher in the EOAD group (n = 18) than in the LOAD group (n = 13). CONCLUSIONS: Multiprobe PET/MRI showed that tau burden and neuronal damage are more severe in EOAD than in LOAD. Multiprobe PET/MRI may be useful to assess the pathologic characteristics of EOAD.

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The second-generation antidepressants (SGAs) are used widely in patients with Alzheimer's disease (AD) for the treatment of mood disorder, sleep disturbance and psychiatric symptoms. Several evidences from AD mice confirmed that antidepressants could delaying cognitive decline. However, the conclusions varied in randomized controlled trials (RCTs) based on patients. This meta-analysis summarizes the cognitive impact of SGAs on AD patients with different neuropsychiatric symptoms (NPS). Results show there is no effect on cognition and depression between SGAs treatment and controls, and this remains in subgroups analyses of duration of medication (<12 weeks or ≥12 weeks), drug classes (SSRIs or non-SSRIs), combination with anti-dementia medication, various NPS, and degree of AD. The available evidence provides no support for the efficacy of SGAs for cognition and depression of AD patients. The implications of the findings and their mechanism relevance are also discussed in this paper.

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PURPOSE: 18F-APN-1607 is a novel tau positron emission tomography (PET) tracer characterized with high binding affinity for 3- and 4-repeat tau deposits. The aim was to analyze the spatial distribution of 18F-APN-1607 PET imaging in Alzheimer's disease (AD) subjects with different stages and to investigate the relationship between the change of tau deposition and overall disease progression. METHODS: We retrospectively analyzed the 18F-APN-1607 PET imaging of 31 subjects with clinically and imaging defined as AD. According to the Mini-Mental State Examination (MMSE) score, patients were divided into three groups, namely, mild (≥21, n = 7), moderate (10-20, n = 16), and severe (≤9, n = 8). PET imaging was segmented to 70 regions of interest (ROIs) and extracted the standard uptake value (SUV) of each ROI. SUV ratio (SUVR) was calculated from the ratio of SUV in different brain regions to the cerebellar cortex. The regions were defined as positive and negative with unsupervised cluster analysis according to SUVR. The SUVRs of each region were compared among groups with the one-way ANOVA or Kruskal-Wallis H test. Furthermore, the correlations between MMSE score and regional SUVR were calculated with Pearson or Spearman correlation analysis. RESULTS: There were no significant differences among groups in gender (χ2 = 3.814, P = 0.161), age of onset (P = 0.170), age (P = 0.109), and education level (P = 0.065). With the disease progression, the 18F-APN-1607 PET imaging showed the spread of tau deposition from the hippocampus, posterior cingulate gyrus (PCG), and lateral temporal cortex (LTC) to the parietal and occipital lobes, and finally to the frontal lobe. Between the mild and moderate groups, the main brain areas with significant differences in 18F-APN-1607 uptake were supplementary motor area (SMA), cuneus, precuneus, occipital lobule, paracentral lobule, right angular gyrus, and parietal, which could be used for early disease progression assessment (P < 0.05). There were significant differences in the frontal lobe, right temporal lobe, and fusiform gyrus between the moderate and severe groups, which might be suitable for the late-stage disease progression assessment (P < 0.05). CONCLUSION: 18F-APN-1607 PET may serve as an effective imaging marker for visualizing the change pattern of tau protein deposition in AD patients, and its uptake level in certain brain regions is closely related to the severity of cognitive impairment. These indicate the potential of 18F-APN-1607 PET for the in vivo evaluation of the progression of AD.

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BACKGROUND: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type. OBJECTIVE: To explore the efficacy and safety of the maximal tolerated dose of rivastigmine capsules in Chinese patients with mild-to-moderate Alzheimer's disease (AD). METHODS: The study was a multicenter, open-label, single-arm, phase IV clinical study in mild-to-moderate drug-naïve AD patients treated with rivastigmine capsules. The primary endpoint was the changes in the total scores of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) from baseline to week 16. Secondary endpoints included changes in the scores of the following assessment scales and safety: Alzheimer's Disease Cooperative Study; Activities of Daily Living; Mini-Mental Status Examination (MMSE); Neuropsychiatry Index (NPI), and Caregiver Burden Inventory. RESULTS: 222 patients were enrolled. Of these, 136 (75.1%) patients received and maintained the effective dose (≥6 mg/d) of rivastigmine for at least 4 weeks. The ADAS-Cog scale score improved in rivastigmine-treated patients at week 16 compared with baseline (p < 0.001) by 2.0 (95% CI: -3.0 to -1.1) points, which met the pre-defined superiority criteria. NPI-10 and NPI-12 scores improved by 3.6 and 4.0 points at week 16 (p = 0.001, p < 0.001), respectively. A total of 107 patients (59.1%) experienced adverse effects (AEs) during the study; common AEs included nausea (20.5%), vomiting (16.6%), anorexia (7.8%), dizziness (7.7%), and diarrhea (7.2%). CONCLUSION: This was the first phase IV study on rivastigmine in mainland China. The study preliminarily demonstrated that rivastigmine capsules showed good tolerability and efficacy in mild-to-moderate AD patients with the maximal tolerated dose.

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BACKGROUND: Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer's disease and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson's disease (PD), the second most common neurodegenerative disorder. METHODS: We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. RESULTS: We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. CONCLUSIONS: miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

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BACKGROUND: Preclinical and clinical evidence suggests that elderly individuals are at increased risk of cognitive decline after general anesthesia. General anesthesia is also believed to be a risk factor for Postoperative Cognitive Dysfunction (POCD) and Alzheimer's Disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, how insulin treatment improves cognitive function is poorly understood. METHODS: Aged mice were pretreated with intranasal insulin or saline before anesthesia. Propofol was added intraperitoneally to the mice from 7th day of insulin/saline treatment, and general anesthesia was induced and maintained for 2 hours/day for 5 consecutive days. Mice were evaluated at 26th day when the mice were continued on insulin or saline administration for another 15 days. RESULTS: We found that intranasal insulin treatment prevented anesthesia-induced cognitive impairments, as measured by novel object recognition test and contextual-dependent fear conditioning test. Insulin treatment also increased the expression level of Post-synaptic Density Protein 95 (PSD95), as well as upregulated Microtubule-associated Protein-2 (MAP-2) in the dentate gyrus of the hippocampus. Furthermore, we found that insulin treatment restored insulin signaling disturbed by anesthesia via activating PI3K/PDK1/AKT pathway, and attenuated anesthesia-induced hyperphosphorylation of tau at multiple AD-associated sites. We found the attenuation of tau hyperphosphorylation occurred by increasing the level of GSK3ß phosphorylated at Ser9, which leads to inactivation of GSK-3ß. CONCLUSION: Intranasal insulin administration might be a promising therapy to prevent anesthesiainduced cognitive deficit in elderly individuals.

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[This corrects the article DOI: 10.1371/journal.pone.0196646.].

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There is a severe lack of aphasia screening tools for bedside use in Chinese. A number of aphasia assessment tools have recently been developed abroad, but some of these scales were not suitable for patients with acute stroke. The Language Screening Test (which includes two parallel versions [a/b]) in French has been proven to be an effective and time-saving aphasia screening scale for early-stage stroke patients. Therefore, we worked out a Chinese version of the LAST taking into consideration Chinese language and culture. Two preliminary parallel versions (a/b) were tested on 154 patients with stroke at acute phase and 107 patients with stroke at non-acute phase, with the Western Aphasia Battery serving as a gold standard. The equivalence between the two parallel versions and the reliability/validity of each version were assessed. The median time to complete one preliminary Chinese version (each had some item redundancy) was 98 seconds. Two final parallel versions were established after adjustment/elimination of the redundant items and were found to be equivalent (intra-class correlation coefficient: 0.991). Internal consistency is(Cronbach α for each version [a/b] was 0.956 and 0.965, respectively) good. Internal validity was fine: (a) no floor or ceiling effect/item redundancy; (b) construct validity revealed a 1-dimension structure, just like the French version. The higher educated subjects scored higher than their lower educated counterparts (p<0.01). The external validity: at the optimum cut-off point where the score of version a/b <14 in higher educated group(<13 in lower): the specificity of each version was 0.878/0.902(1/1 in lower) and sensitivity was 0.972/0.944(0.944/0.944 in lower). Inter-rater equivalence (intra-class correlation coefficient) was 1. The Chinese version of the Language Screening Test was proved to be an efficient and time-saving bedside aphasia screening tool for stroke patients at acute phase and can be used by an average medical physician.

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Decreased brain insulin signaling has been found recently in Alzheimer's disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, the underlying mechanisms are unknown. Here, we treated 9-month-old 3xTg-AD mice, a commonly used mouse model of AD, with daily intranasal administration of insulin for seven days and then studied brain abnormalities of the mice biochemically and immunohistochemically. We found that intranasal insulin restored insulin signaling, increased the levels of synaptic proteins, and reduced Aß40 level and microglia activation in the brains of 3xTg-AD mice. However, this treatment did not affect the levels of glucose transporters and O-GlcNAcylation or tau phosphorylation. Our findings provide a mechanistic insight into the beneficial effects of intranasal insulin treatment and support continuous clinical trials of intranasal insulin for the treatment of AD.

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BACKGROUND: It is well documented that elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer's disease (AD). Recent studies suggest that anesthesia may increase the risk for cognitive decline and AD through promoting abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration seen in AD. METHODS: We treated 3xTg-AD mice, a commonly used transgenic mouse model of AD, with daily intranasal administration of insulin (1.75 U/day) for one week. The insulin- and control-treated mice were then anesthetized with single intraperitoneal injection of propofol (250 mg/kg body weight). Tau phosphorylation and tau protein kinases and phosphatases in the brains of mice 30 min and 2 h after propofol injection were then investigated by using Western blots and immunohistochemistry. RESULTS: Propofol strongly promoted hyperphosphorylation of tau at several AD-related phosphorylation sites. Intranasal administration of insulin attenuated propofol-induced hyperphosphorylation of tau, promoted brain insulin signaling, and led to up-regulation of protein phosphatase 2A, a major tau phosphatase in the brain. Intranasal insulin also resulted in down-regulation of several tau protein kinases, including cyclin-dependent protein kinase 5, calcium/calmodulin-dependent protein kinase II, and c-Jun N-terminal kinase. CONCLUSION: Our results demonstrate that pretreatment with intranasal insulin prevents AD-like tau hyperphosphorylation. These findings provide the first evidence supporting that intranasal insulin administration might be used for the prevention of anesthesia-induced cognitive decline and increased risk for AD and dementia.

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Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aß accumulation, 3-6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase in tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease in synaptic plasticity and amyloid ß peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.

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AIMS: Anesthesia is related to cognitive impairment and the risk for Alzheimer's disease. Hypothermia during anesthesia can lead to abnormal hyperphosphorylation of tau, which has been speculated to be involved in anesthesia-induced cognitive impairment. The aim of this study was to investigate whether maintenance of the tau phosphorylation level by body temperature control during anesthesia could reverse the cognitive dysfunction in C57BL/6 mice. METHODS: Eighteen-month-old mice were repeatedly anesthetized during a 2-week period with or without maintenance of body temperature, control mice were treated with normal saline instead of anesthetics. Tau phosphorylation level in mice brain was detected on western blot, and cognitive performance was measured using the Morris water maze (MWM). RESULTS: After anesthesia-induced hypothermia in old mice, tau was hyperphosphorylated and the cognitive performance, measured on MWM, was impaired. When body temperature was controlled during anesthesia, however, the tau hyperphosphorylation was completely avoided, and there was partial recovery in cognitive impairment measured on the MWM. CONCLUSION: Hyperphosphorylation of tau in the brain after anesthesia is an important event, and it might be, although not solely, responsible for postoperative cognitive decline.

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Preventing or reducing tau hyperphosphorylation is considered to be a therapeutic strategy in the treatment of Alzheimer's disease (AD). Rapamycin may be a potential therapeutic agent for AD, because the rapamycin-induced autophagy may enhance the clearance of the hyperphosphorylated tau. However, recent rodent studies show that the protective effect of rapamycin may not be limited in the autophagic clearance of the hyperphosphorylated tau. Because some tau-related kinases are targets of the mammalian target of rapamycin (mTOR), we assume that rapamycin may regulate tau phosphorylation by regulating these kinases. Our results showed that in human neuroblastoma SH-SY5Y cells, treatment with rapamycin induced phosphorylation of the type IIα regulatory (RIIα) subunit of cAMP-dependent kinase (PKA). Rapamycin also induced nuclear translocation of the catalytic subunits (Cat) of PKA and decreases in tau phosphorylation at Ser214 (pS214). The above effects of rapamycin were prevented by pretreatment with the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126. In addition, these effects of rapamycin might not depend on the level of tau expression, because similar results were obtained in both the non-tau-expressing wild type human embryonic kidney 293 (HEK293) cells and HEK293 cells stably transfected with the longest isoform of recombinant human tau (tau441; HEK293/tau441). These findings suggest that rapamycin decreases pS214 via regulation of PKA. Because tau phosphorylation at Ser214 may prime tau for further phosphorylation by other kinases, our findings provide a novel possible mechanism by which rapamycin reduces or prevents tau hyperphosphorylation.

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Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-ß (Aß) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

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It is believed that estrogen protects neurons against various toxicities like that from amyloid ß (Aß) in Alzheimer's disease (AD). In the present study, we investigated the effects of Aß1-42 on the activities of cyclic-AMP response element-binding protein (CREB) and glycogen synthase kinase-3ß (GSK-3ß), two key proteins associated with learning and memory, and the effects of 17ß-estradiol on Aß(1-42)-induced changes of CREB and GSK-3ß in PC12 cells. We found that Aß1-42 induced a decrease in phosphorylation of CREB at Ser133 (CREB pS133) and caused a transient (30 min) up-regulation of the inhibitory GSK-3ß phosphorylation at Ser9 (GSK-3ß pS9), followed by down-regulation of GSK-3ß pS9. Pretreatment of 17ß-estradiol is needed for its protection against Aß1-42-induced changes of CREB. The protective role of 17ß-estradiol against Aß(1-42)-induced down-regulation of CREB pS133 was abolished by the mitogen-activated protein kinase (MAPK) pathway inhibitor U0126. Furthermore, 17ß-estradiol also prolonged the up-regulation of GSK-3ß pS9 for at least 8 h. However, this action of 17ß-estradiol was abrogated by PKA inhibitor H-89, AKT inhibitor LY294002, and MAPK inhibitor U0126. These results suggest that, while the protection of 17ß-estradiol on CREB is MAPK dependent, its effect on GSK-3ß integrates several pathways. These studies provide new insights into the role of estrogen in memory and AD.

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Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and may result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations of presenilins or amyloid-ß (Aß) precursor protein (APP). A commonly used mouse model for AD is 3xTg-AD mouse, which is generated by over-expression of mutated presenilin 1, APP and tau in the brain and thus represents a mouse model of FAD. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse, shows many aspects of SAD. Despite the wide use of these two models for AD research, differences in gene expression between them are not known. Here, we compared the expression of 84 AD-related genes in the hippocampus and the cerebral cortex between icv-STZ mice and 3xTg-AD mice using a custom-designed qPCR array. These genes are involved in APP processing, tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related protein kinases, glucose metabolism, insulin signaling, and mTOR pathway. We found altered expression of around 20 genes in both mouse models, which affected each of above categories. Many of these gene alterations were consistent with what was observed in AD brain previously. The expression of most of these altered genes was decreased or tended to be decreased in the hippocampus of both mouse models. Significant diversity in gene expression was found in the cerebral cortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the 3xTg-AD mice, whereas more genes related to insulin signaling and glucose metabolism were down-regulated in the icv-STZ mice. The present study provides important fundamental knowledge of these two AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

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