Myeloid ectopic viral integration site 2 accelerates the progression of Alzheimer's disease.

Amyloid plaques, a major pathological hallmark of Alzheimer's disease (AD), are caused by an imbalance between the amyloidogenic and non-amyloidogenic pathways of amyloid precursor protein (APP). BACE1 cleavage of APP is the rate-limiting step for amyloid-ß production and plaque formation in AD. Although the alteration of BACE1 expression in AD has been investigated, the underlying mechanisms remain unknown. In this study, we determined MEIS2 was notably elevated in AD models and AD patients. Alterations in the expression of MEIS2 can modulate the levels of BACE1. MEIS2 downregulation improved the learning and memory retention of AD mice and decreased the number of amyloid plaques. MEIS2 binds to the BACE1 promoter, positively regulates BACE1 expression, and accelerates APP amyloid degradation in vitro. Therefore, our findings suggest that MEIS2 might be a critical transcription factor in AD, since it regulates BACE1 expression and accelerates BACE1-mediated APP amyloidogenic cleavage. MEIS2 is a promising early intervention target for AD treatment.

Synaptic vesicle glycoprotein 2 A in serum is an ideal biomarker for early diagnosis of Alzheimer's disease.

BACKGROUND: Previous studies have demonstrated that early intervention was the best plan to inhibit the progression of Alzheimer's disease (AD), which relied on the discovery of early diagnostic biomarkers. In this study, synaptic vesicle glycoprotein 2 A (SV2A) was examined to improve the early diagnostic efficiency in AD. METHODS: In this study, biomarker testing was performed through the single-molecule array (Simoa). A total of 121 subjects including cognitively unimpaired controls, amnestic mild cognitive impairment (aMCI), AD and other types of dementia underwent cerebrospinal fluid (CSF) SV2A testing; 430 subjects including health controls, aMCI, AD and other types of dementia underwent serum SV2A, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and p-tau217 testing; 92 subjects including aMCI and AD underwent both CSF SV2A and serum SV2A testing; 115 cognitively unimpaired subjects including APOE ε4 carriers and APOE ε4 non-carriers were tested for serum SV2A, GFAP, NfL and p-tau217. Then, the efficacy of SV2A for the early diagnosis of AD and its ability to identify those at high risk of AD from a cognitively unimpaired population were further analyzed. RESULTS: Both CSF and serum SV2A significantly and positively correlated with cognitive performance in patients with AD, and their levels gradually decreased with the progression of AD. Serum SV2A demonstrated excellent diagnostic efficacy for aMCI, with a sensitivity of 97.8%, which was significantly higher than those of NfL, GFAP, and p-tau217. The SV2A-positive rates ranged from 92.86 to 100% in aMCI cases that were negative for the above three biomarkers. Importantly, of all the biomarkers tested, serum SV2A had the highest positivity rate (81.82%) in individuals at risk for AD. CONCLUSIONS: Serum SV2A was demonstrated to be a novel and ideal biomarker for the early diagnosis of AD, which can effectively distinguish those at high risk of AD in cognitively unimpaired populations.

IL-17A promotes the progression of Alzheimer's disease in APP/PS1 mice.

BACKGROUND: Alzheimer's disease (AD), which is the most common cause of dementia in elderly individuals, is a progressive neurodegenerative disorder. Neuroinflammation, which is an immune response that is activated by glial cells in the central nervous system, plays an important role in neurodegenerative diseases. Many studies have shown that interleukin-17A (IL-17A) plays an important role in AD, but research on the pathological effects of IL-17A on AD is limited. METHODS: We report the effect of IL-17A on AD progression in APPswe/PS1dE9 (APP/PS1) mice, which are the most widely used AD model mice. The BV2 cell line, which is a microglial cell line derived from C57/BL6 mice, was used to establish a cell model to verify the role of IL-17A in neuroinflammation at the cellular level. The HT22 hippocampal neuronal cell line was used to investigate the relationship between IL-17A and Aß deposition. RESULTS: In this research, we found that IL-17A promotes the progression of AD in the APP/PS1 mouse model. The role of IL-17A in neuroinflammation is related to tumour necrosis factor (TNF)-α. Circulating IL-17A stimulates the secretion of TNF-α by microglia through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signalling pathway, thus exacerbating neuroinflammation. In addition, intraperitoneal injection of IL-17A antibody (IL17Ab) significantly improved the cognitive function of APP/PS1 mice. CONCLUSIONS: IL-17A increased TNF-α levels in the brain and exacerbated neuroinflammation through the TLR4/NF-κB signalling pathway and microglial activation in APP/PS1 mice. Moreover, IL-17A promoted the progression of AD by enhancing neuroinflammation, inhibiting microglial phagocytosis, and promoting the deposition of ß-amyloid 42 in AD model mice.

Factors influencing the degree of disability in patients with neuromyelitis optica spectrum disorders.

OBJECTIVE: To investigate the factors influencing the degree of disability in patients with neuromyelitis optica spectrum disorder (NMOSD) and provide evidence for disease monitoring and clinical intervention. METHODS: Eighty-four patients with NMOSD at Xuanwu Hospital Capital Medical University were enrolled in this retrospective study. Before treatment, blood was collected from all patients, and their expanded disability status scores were assessed. RESULTS: Of the 84 patients assessed, 66 (78.57%) had an expanded disability status scale score < 7, and 18 (21.43%) had scores ≥ 7. The univariate analysis showed that the total bilirubin (TBil), cerebrospinal fluid albumin (CSF ALB), cerebrospinal fluid immunoglobulin G (CSF IgG), QALB, and QIgG levels in the group with scores ≥ 7 were significantly different from those with scores < 7 (P < 0.05). In addition, Spearman's correlation analysis showed a significant correlation between ALB and expanded disability status scores in patients with NMOSD (P < 0.05), and the multivariate logistic regression analysis showed that TBil was an independent factor influencing the degree of disability in patients with NMOSD (P < 0.05). The receiver operating characteristic curve was constructed using TBil values; the area under the curve of TBil was 0.729 (P < 0.01), and the best cut-off value was 11.015 g/L. Its sensitivity in predicting the severity of disability in NMOSD patients was 51.5% while its specificity was 88.9%. CONCLUSION: TBil is an independent factor that influences the severity of disability in patients with NMOSD. In addition, ALB is closely related to NMOSD severity, and some factors associated with the BBB are significantly increased in severely disabled NMOSD patients.

Downregulation of Krüppel-like factor 14 accelerated cellular senescence and aging.

Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether Krüppel-like factor 14 (KLF14) is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6J mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1 expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in senescence-accelerated P8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14's transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

The Interpretation of Mirror Pattern Bands During Oligoclonal Immunoglobulin Isoelectric Focusing Electrophoresis: A Retrospective Study.

OBJECTIVE: Mirror patterns are incidental types that accompany the analysis of the oligoclonal band (OCB) in cerebrospinal fluid (CSF). However, their interpretation remains controversial. In this study, we analyzed all graphic results of mirror patterns from 86 patients to provide an optimal interpretation scheme for mirror patterns. METHODS: Matched CSF and serum specimens were obtained from patients with various neurological disorders that required OCB analysis. A total of 86 patients were screened and serum immunofixation electrophoresis (IFE) was performed in all 86. The interobserver agreement for interpreting mirror patterns by visual inspection was tested. The method agreement between the visual inspection and IFE was also evaluated. The CSF/serum albumin quotient (QALB) was calculated to determine the blood-brain barrier integrity of all patients. RESULTS: Of the 86 patients with mirror patterns, 19.8% (17/86) had typical mirror bands and most (80.2%) had atypical mirror bands. There was a good agreement between the 2 observers in interpreting typical mirror patterns. However, kappa statistics analysis showed poor agreement regarding the interpretation of atypical mirror bands by visual observation alone (kappa value, -0.026 to 0.314 between 2 observers). The disagreement was pronounced between the visual inspection and validation of IFE (kappa value, -0.0238 to 0.176 between the first observer and IFE; -0.322 to 0.118 between the second observer and IFE). The normal QALB rates in the type V groups were significantly higher than those in the type IV group and the positive QALB rates in the type IV were significantly higher than those in the type V. CONCLUSION: Visual inspection to interpret mirror pattern bands is unreliable. Considering the completely different clinical significance between type IV and type V and high risk of potential misinterpretations, it is necessary to perform IFE on all the atypical mirror types to discriminate atypical type IV from atypical type V.

Integrated multi-omics approach revealed cellular senescence landscape.

Cellular senescence is a complex multifactorial biological phenomenon that plays essential roles in aging, and aging-related diseases. During this process, the senescent cells undergo gene expression altering and chromatin structure remodeling. However, studies on the epigenetic landscape of senescence using integrated multi-omics approaches are limited. In this research, we performed ATAC-seq, RNA-seq and ChIP-seq on different senescent types to reveal the landscape of senescence and identify the prime regulatory elements. We also obtained 34 key genes and deduced that NAT1, PBX1 and RRM2, which interacted with each other, could be the potential markers of aging and aging-related diseases. In summary, our work provides the landscape to study accessibility dynamics and transcriptional regulations in cellular senescence. The application of this technique in different types of senescence allows us to identify the regulatory elements responsible for the substantial regulation of transcription, providing the insights into molecular mechanisms of senescence.

Krüppel-like factor 5 accelerates the pathogenesis of Alzheimer's disease via BACE1-mediated APP processing.

BACKGROUND: The deposition of ß-amyloid (Aß) in the brain plays a major role in the pathogenesis of Alzheimer's disease (AD). Aß is generated via amyloid precursor protein (APP) cleavage through the amyloidogenic pathway. In this pathway, ß-secretase (BACE1) is the first and rate-limiting enzyme. Its expression increases through an unknown mechanism in patients with AD. Thus, the key regulatory mechanism of BACE1 in the AD process should be revealed to understand the pathogenesis of AD and explore the key treatment targets of AD. METHODS: Here, APPswe/PS1dE9 (APP/PS1) mice were employed to observe the Krüppel-like factor 5 (KLF5) and BACE1 levels in the serum and brain tissues. HT22 cells were used to explore the relationship between KLF5 and BACE1. RESULTS: In this study, KLF5 was found to be a novel transcription factor that positively regulated BACE1 by binding to the BACE1 promoter. The KLF5 levels significantly increased not only in the CSF and serum of patients with AD but also in the brain tissue of APP/PS1 mice. They were closely related to cognitive capacity. KLF5 accelerated APP amyloidogenic metabolism and promoted Aß synthesis through BACE1. Silencing BACE1 could block the KLF5-induced amyloidogenic process of APP. ML264 ameliorated the cognitive deficits and slowed down APP amyloidogenic cleavage in APP/PS1 mice. CONCLUSION: The findings above suggest that upregulation of KLF5 might be a critical element in AD progression by accelerating BACE1-mediated APP amyloidogenic cleavage. The inhibition of KLF5 or the combined inhibitory effect of KLF5 and the BACE1 promoter might be a potential strategy to prevent AD pathogenesis.

ABI3 Is a Novel Early Biomarker of Alzheimer's Disease.

BACKGROUND: The Abi3 gene has been suggested to be an important regulator of microglia during Alzheimer's disease (AD), but the diagnostic power of ABI3 in neurodegenerative disease has rarely been reported. OBJECTIVE: The aim of this study was to evaluate the diagnostic value of ABI3 in AD patients. METHODS: ELISAs were used to measure the ABI3 level in the serum and cerebrospinal fluid (CSF) of AD patients as well as in the serum of APP/PS1 mice. RT-PCR and western blot were further performed to detect the expression levels of ABI3 in peripheral blood mononuclear cells (PBMCs) of AD subjects as well as in the hippocampus and cortical tissue of APP/PS1 mice. The correlation of cognitive ability with ABI3 level was estimated by linear regression analysis. Moreover, the diagnostic value of ABI3 for AD was assessed with ROC analysis. RESULTS: The ABI3 levels all decreased significantly in the serum, CSF, and PBMCs of AD patients and showed a good diagnostic performance. In addition, the ABI3 levels were observed to decrease markedly in the hippocampus from 5-month-old mice, but the dramatic change only appeared in the cortical tissue in the 9-month-old APP/PS1 mice. The ABI3 levels in serum and in the hippocampus of APP/PS1 mice were significantly correlated with cognitive capacity. CONCLUSION: These results demonstrated that ABI3 in serum, CSF, and PBMCs could be a novel early diagnostic biomarker of AD. Moreover, ABI3 had potential to be a novel tracer marker in hippocampus of early AD.

ABCA1-Labeled Exosomes in Serum Contain Higher MicroRNA-193b Levels in Alzheimer's Disease.

OBJECTIVE: We aimed to establish a method to determine whether microRNA-193b (miR-193b) levels in ABCA1-labeled serum exosomes might serve as a marker for the diagnosis of Alzheimer's disease. METHODS: We used immunocapture methods to determine the levels of ABCA1-labeled exosomal miR-193b in cultures of white blood cells (WBCs), red blood cells (RBCs), mouse hippocampal neuron HT-22 cells, and primary mouse neuronal cells. ABCA1-labeled exosomal miR-193b levels were also evaluated in the cerebrospinal fluid (CSF) and serum of APP/PS1 double-transgenic mice, as well as control subjects (n = 60) and study participants with subjective cognitive decline (SCD, n = 89), stage and mild cognitive impairment (MCI, n = 92), and dementia of the Alzheimer type (DAT, n = 92). RESULTS: ABCA1 levels of exosomes harvested from the medium of HT-22 cells and neurons were significantly higher than those of RBCs and WBCs (P < 0.05). Exosomal ABCA1 from the CSF of APP/PS1 mice were transmitted to the serum of wild-type mice after injection, and high miR-193b levels were observed in both the serum and CSF after injection. The ABCA1-labeled exosomal miR-193b levels were higher in the CSF of MCI and DAT patients compared with the CSF of the control group (P < 0.05). The ABCA1-labeled exosomal miR-193b were also slightly higher (P > 0.05) in the serum of SCD patients and significantly higher in the serum of MCI and DAT patients compared with the serum of the control group (P < 0.05). CONCLUSION: This study provides a method to capture specific exosomes. Detection of serum exosomes labeled with ABCA1 may facilitate the early diagnosis of AD.

CTCF Mediates Replicative Senescence Through POLD1.

POLD1, the catalytic subunit of DNA polymerase δ, plays a critical role in DNA synthesis and DNA repair processes. Moreover, POLD1 is downregulated in replicative senescence to mediate aging. In any case, the components of age-related downregulation of POLD1 expression have not been fully explained. In this article, we elucidate the mechanism of the regulation of POLD1 at the transcription level and found that the transcription factor CCCTC-binding factor (CTCF) was bound to the POLD1 promoter area in two sites. The binding level of CTCF for the POLD1 promoter appeared to be related to aging and was confirmed to be positively controlled by the CTCF level. Additionally, cell senescence characteristics were detected within the cells transfected with short hairpin RNA (shRNA)-CTCF, pLenti-CMV-CTCF, shRNA-POLD1, and pLenti-CMV-POLD1, and the results showed that the CTCF may contribute to the altered expression of POLD1 in aging. In conclusion, the binding level of CTCF for the POLD1 promoter intervened by an age-related decrease in CTCF and downregulated the POLD1 expression in aging. Moreover, the decrease in CTCF-mediated POLD1 transcription accelerates the progression of cell aging.

Severely High Lactic Acid in Severe Pneumonia Patient: a Case Report.

BACKGROUND: Severe pneumonia (SP) is a clinically critical acute disease which has a higher mortality rate among infectious diseases. In this report, a rare case of severe pneumonia with severely high lactic acid (up to 24 mmol/L) and relatively normal pH was analyzed. METHODS: The case was discussed from different angles including acid-base balance disorder, the use of extractor-poreal membrane oxygenation (ECMO), dialysis treatment, circulatory disturbance, and inspection methodology. RESULTS: Hypoxia and dissolution of muscles caused by circulatory disorders may be the cause of the abnormal increase of lactate in this case; while the relatively normal pH may be caused by the dialysis treatment. CONCLUSIONS: Such a high blood gas lactic acid value is extremely rare, and this increase is not due to the limitations of the test method. High lactic acid may not result in the significant decrease of pH when the patient receives continuous systemic treatment.

Identification by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and Antifungal Susceptibility Testing of Non-Aspergillus Molds.

Non-Aspergillus molds including Mucorales, Fusarium, and Scedosporium, etc. are emerging pathogens leading to higher mortality in immunocompromised patients. Fifty-two isolates of genetically confirmed non-Aspergillus molds representing 16 species from 8 genera were collected to evaluate the performance of the Bruker matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in identification of non-Aspergillus molds. Antifungal susceptibilities were determined through the Clinical & Laboratory Standards Institute (CLSI) M38-A2 broth microdilution method and the Sensititre YeastOne colorimetric method. Bruker MALDI-TOF MS identified 57.7% (30/52) of isolates cultured in broth and 15.4% (8/52) of isolates cultured on solid agar media to the species level, respectively, according to standard interpretation criteria. Lowering the species level cut-off value (COV) from ≥2.0 to ≥1.7 could improve the MALDI-TOF MS species-level identification rate to 67.3% (38/52) for isolates cultured on solid media, with a slight increase of false identification rate of 2.6% (1/38). Amphotericin B was the most in vitro fungistatic-active agent for 98.1% (51/52) of the tested non-Aspergillus molds, with minimum inhibitory concentrations (MICs) of ≤2 µg/mL. The susceptibilities to triazoles varied, with MICs of 0.12 to >16 µg/mL among different species of non-Aspergillus molds. The correlation between the CLSI method and Sensititre YeastOne on antifungal susceptibility testing of non-Aspergillus molds was good, with essential agreement (EA) rates of >90% for triazoles and echinocandins except amphotericin B, which had a lower EA rate of 84.6%. In conclusion, a favorable performance of the Bruker MALDI-TOF MS in identification of clinical non-Aspergillus isolates directly inoculated on solid agar media could be achieved with the adoption of alternative interpretation criteria. Antifungal susceptibility testing is important for non-Aspergillus molds, especially when information on triazole susceptibility is required, and the Sensititre YeastOne is a practical and reliable method to determine antifungal susceptibilities of non-Aspergillus molds.

Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation.

BACKGROUND: Fanconi anemia (FA) is a rare recessive disease characterized by DNA damage repair deficiency, and DNA polymerase δ (whose catalytic subunit is encoded by POLD1, also known as CDC2) is closely related to DNA damage repair. Our previous study identified a novel POLD1 missense mutation c.56G>A (p. Arg19>His) in FA family members. However, the function of the POLD1 missense mutation is currently unknown. This study aimed to uncover the biological function of the POLD1 missense mutation. METHODS: Stable cell lines overexpressing wild-type POLD1 or mutant POLD1 (c.56G>A, p.Arg19His) were constructed by lentivirus infection. Cell growth curve analysis, cell cycle analysis, and a comet assay were used to analyze the function of the POLD1 mutation. RESULTS: The growth and proliferative ability of the cells with POLD1 mutation was decreased significantly compared with those of the wild-type cells (Student's t test, p < .05). The percentage of cells in the G0/G1 phase increased, and the percentage of cells in the S phase decreased significantly when POLD1 was mutated (Student's t test, p < .05). Moreover, the Olive tail moment value of the cells with the POLD1 mutation was significantly higher than that of the cells with wild-type POLD1 after H2 O2 treatment. CONCLUSIONS: The POLD1 mutation inhibited cell proliferation, slowed cell cycle progression, and reduced DNA damage repair.

Characterization of the chromatin accessibility in an Alzheimer's disease (AD) mouse model.

BACKGROUND: The pathological hallmarks of Alzheimer's disease (AD) involve alterations in the expression of numerous genes associated with transcriptional levels, which are determined by chromatin accessibility. Here, the landscape of chromatin accessibility was studied to understand the outline of the transcription and expression of AD-associated metabolism genes in an AD mouse model. METHODS: The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA sequencing. Gene ontology (GO) analysis was applied to elucidate biological processes and signaling pathways altered in APP/PS1 mice. Critical transcription factors were identified; alterations in chromatin accessibility were further confirmed using chromatin immunoprecipitation assays. RESULTS: We identified 1690 increased AD-associated chromatin-accessible regions in the hippocampal tissues of APP/PS1 mice. These regions were enriched in genes related to diverse signaling pathways, including the PI3K-Akt, Hippo, TGF-ß, and Jak-Stat signaling pathways, which play essential roles in regulating cell proliferation, apoptosis, and inflammatory responses. A total of 1003 decreased chromatin-accessible regions were considered to be related with declined AD-associated biological processes including cellular response to hyperoxia and insulin stimulus, synaptic transmission, and positive regulation of autophagy. In the APP/PS1 hippocampus, 1090 genes were found to be upregulated and 1081 downregulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting upregulated mRNA levels. Several genes involved in AD development were found to have a significantly increased expression in APP/PS1 mice compared to controls, including Sele, Clec7a, Cst7, and Ccr6. The signatures of numerous transcription factors, including Olig2, NeuroD1, TCF4, and NeuroG2, were found enriched in the AD-associated accessible chromatin regions. The transcription-activating marks of H3K4me3 and H3K27ac were also found increased in the promoters of these genes. These results indicate that the mechanism for the upregulation of genes could be attributed to the enrichment of open chromatin regions with transcription factors motifs and the histone marks H3K4me3 and H3K27ac. CONCLUSION: Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.

Multi-sensor integration approach based on hyperspectral imaging and electronic nose for quantitation of fat and peroxide value of pork meat.

The study assessed the feasibility of merging data acquired from hyperspectral imaging (HSI) and electronic nose (e-nose) to develop a robust method for the rapid prediction of intramuscular fat (IMF) and peroxide value (PV) of pork meat affected by temperature and NaCl treatments. Multivariate calibration models for prediction of IMF and PV using median spectra features (MSF) and image texture features (ITF) from HSI data and mean signal values (MSV) from e-nose signals were established based on support vector machine regression (SVMR). Optimum wavelengths highly related to IMF and PV were selected from the MSF and ITF. Next, recurring optimum wavelengths from the two feature groups were manually obtained and merged to constitute "combined attribute features" (CAF) which yielded acceptable results with (Rc2 = 0.877, 0.891; RMSEC = 2.410, 1.109; Rp2 = 0.790, 0.858; RMSEP = 3.611, 2.013) respectively for IMF and PV. MSV yielded relatively low results with (Rc2 = 0.783, 0.877; RMSEC = 4.591, 0.653; Rp2 = 0.704, 0.797; RMSEP = 3.991, 0.760) respectively for IMF and PV. Finally, data fusion of CAF and MSV was performed which yielded relatively improved prediction results with (Rc2 = 0.936, 0.955; RMSEC = 1.209, 0.997; Rp2 = 0.895, 0.901; RMSEP = 2.099, 1.008) respectively for IMF and PV. The results obtained demonstrate that it is feasible to mutually integrate spectral and image features with volatile information to quantitatively monitor IMF and PV in processed pork meat. Graphical abstract.

Role of monocarboxylate transporter 4 in Alzheimer disease.

The pathological process of Alzheimer disease (AD) is closely related to energy metabolism disorders. In the nervous system, monocarboxylate transporter 4 (MCT4) is expressed in the glial cell membrane and is responsible for transporting intracellular lactic acid. In this study, we found that MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment. Two- and three-month-old APPswe/PS1dE9 (APP/PS1) mice and C57 mice were studied. The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice. This change is similar to that in people with mild cognitive impairment. Subsequently, MCT4 overexpression/siRNA lentiviral particles were used to establish stable primary astrocytes. Overexpression and knockdown of MCT4 had no significant effect on glial cell apoptosis. Transfected astrocytes were co-cultured with neurons. Overexpression of cytoplasmic MCT4 increased the expression of Aß42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased. In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression. Taken together, these results suggest that MCT4 is involved in energy metabolism during early pathological processes in AD, and suppression of MCT4 represents a new potential neuroprotective factor for AD.