UCP2 inhibition induces ROS/Akt/mTOR axis: Role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism.
Dando Ilaria,Pacchiana Raffaella,Pozza Elisa Dalla,Cataldo Ivana,Bruno Stefano,Conti Paola,Cordani Marco,Grimaldi Anna,Butera Giovanna,Caraglia Michele,Scarpa Aldo,Palmieri Marta,Donadelli Massimo
Free radical biology & medicine
Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma.
10.1016/j.freeradbiomed.2017.09.022
Small molecules preventing GAPDH aggregation are therapeutically applicable in cell and rat models of oxidative stress.
Lazarev Vladimir F,Nikotina Alina D,Semenyuk Pavel I,Evstafyeva Diana B,Mikhaylova Elena R,Muronetz Vladimir I,Shevtsov Maxim A,Tolkacheva Anastasia V,Dobrodumov Anatoly V,Shavarda Alexey L,Guzhova Irina V,Margulis Boris A
Free radical biology & medicine
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is one of the most abundant targets of the oxidative stress. Oxidation of the enzyme causes its inactivation and the formation of intermolecular disulfide bonds, and leads to the accumulation of GAPDH aggregates and ultimately to cell death. The aim of this work was to reveal the ability of chemicals to break the described above pathologic linkage by inhibiting GAPDH aggregation. Using the model of oxidative stress based on SK-N-SH human neuroblastoma cells treated with hydrogen peroxide, we found that lentivirus-mediated down- or up-regulation of GAPDH content caused inhibition or enhancement of the protein aggregation and respectively reduced or increased the level of cell death. To reveal substances that are able to inhibit GAPDH aggregation, we developed a special assay based on dot ultrafiltration using the collection of small molecules of plant origin. In the first round of screening, five compounds were found to possess anti-aggregation activity as established by ultrafiltration and dynamic light scattering; some of the substances efficiently inhibited GAPDH aggregation in nanomolar concentrations. The ability of the compounds to bind GAPDH molecules was proved by the drug affinity responsive target stability assay, molecular docking and differential scanning calorimetry. Results of experiments with SK-N-SH human neuroblastoma treated with hydrogen peroxide show that two substances, RX409 and RX426, lowered the degree of GAPDH aggregation and reduced cell death by 30%. Oxidative injury was emulated in vivo by injecting of malonic acid into the rat brain, and we showed that the treatment with RX409 or RX426 inhibited GAPDH-mediated aggregation in the brain, reduced areas of the injury as proved by magnetic resonance imaging, and augmented the behavioral status of the rats as established by the "beam walking" test. In conclusion, the data show that two GAPDH binders could be therapeutically relevant in the treatment of injuries stemming from hard oxidative stress.
10.1016/j.freeradbiomed.2015.12.025
Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Aggregation Causes Mitochondrial Dysfunction during Oxidative Stress-induced Cell Death.
Nakajima Hidemitsu,Itakura Masanori,Kubo Takeya,Kaneshige Akihiro,Harada Naoki,Izawa Takeshi,Azuma Yasu-Taka,Kuwamura Mitsuru,Yamaji Ryouichi,Takeuchi Tadayoshi
The Journal of biological chemistry
Glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that also mediates cell death under oxidative stress. We reported previously that the active-site cysteine (Cys-152) of GAPDH plays an essential role in oxidative stress-induced aggregation of GAPDH associated with cell death, and a C152A-GAPDH mutant rescues nitric oxide (NO)-induced cell death by interfering with the aggregation of wild type (WT)-GAPDH. However, the detailed mechanism underlying GAPDH aggregate-induced cell death remains elusive. Here we report that NO-induced GAPDH aggregation specifically causes mitochondrial dysfunction. First, we observed a correlation between NO-induced GAPDH aggregation and mitochondrial dysfunction, when GAPDH aggregation occurred at mitochondria in SH-SY5Y cells. In isolated mitochondria, aggregates of WT-GAPDH directly induced mitochondrial swelling and depolarization, whereas mixtures containing aggregates of C152A-GAPDH reduced mitochondrial dysfunction. Additionally, treatment with cyclosporin A improved WT-GAPDH aggregate-induced swelling and depolarization. In doxycycline-inducible SH-SY5Y cells, overexpression of WT-GAPDH augmented NO-induced mitochondrial dysfunction and increased mitochondrial GAPDH aggregation, whereas induced overexpression of C152A-GAPDH significantly suppressed mitochondrial impairment. Further, NO-induced cytochrome release into the cytosol and nuclear translocation of apoptosis-inducing factor from mitochondria were both augmented in cells overexpressing WT-GAPDH but ameliorated in C152A-GAPDH-overexpressing cells. Interestingly, GAPDH aggregates induced necrotic cell death via a permeability transition pore (PTP) opening. The expression of either WT- or C152A-GAPDH did not affect other cell death pathways associated with protein aggregation, such as proteasome inhibition, gene expression induced by endoplasmic reticulum stress, or autophagy. Collectively, these results suggest that NO-induced GAPDH aggregation specifically induces mitochondrial dysfunction via PTP opening, leading to cell death.
10.1074/jbc.M116.759084
Disclosure of a pro-apoptotic glyceraldehyde-3-phosphate dehydrogenase promoter: anti-dementia drugs depress its activation in apoptosis.
Tsuchiya Katsumi,Tajima Hisao,Yamada Mitsunori,Takahashi Hitoshi,Kuwae Toyoyasu,Sunaga Katsuyoshi,Katsube Nobuo,Ishitani Ryoichi
Life sciences
Overexpression and subsequent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is involved in neuronal apoptosis induced by several stimuli in which GAPDH antisense oligonucleotides specifically block the increment (2 approximately 3 fold) of GAPDH mRNA contents occurring prior to neuronal death. However, these agents do not affect the basal, constitutive mRNA contents. This suggests that there may be distinct gene regulations for GAPDH mRNA expression. Herein, we cloned two types of promoter regions upstream of this gene; viz., #104 (1.02-kb) and #302 (2.46-kb). These fragments were inserted into the pGL3 luciferase reporter system and transiently transfected into cultured cerebellar neurons undergoing cytosine arabinonucleoside-induced apoptosis. The functional analysis of these constructs revealed that #104, but not #302, increased luciferase activity in response to the apoptotic stimulus. Deletion and replacement mutation analysis of the #104 fragment disclosed the promoter core harbored between the 154-bp and 84-bp domains (3.5-fold activity of the control). Furthermore, anti-dementia drugs (such as Cognex and Aricept) markedly depress the expression of this pro-apoptotic GAPDH promoter activity. Interestingly, immunocytochemical examination of human post-mortem materials from patients with Alzheimer's disease revealed nuclear aggregated GAPDH in neurons of the affected brain regions, implying an association with apoptotic cell death. The current findings indicate that induction of the pro-apoptotic protein GAPDH is genetically regulated at the level of promoter activation, and this protein may be an important molecular target for developing anti-apoptotic therapeutic agents in certain neurological illnesses.
10.1016/j.lfs.2003.11.029
Proteomics analysis of the Alzheimer's disease hippocampal proteome.
Sultana Rukhsana,Boyd-Kimball Debra,Cai Jain,Pierce William M,Klein Jon B,Merchant Michael,Butterfield D Allan
Journal of Alzheimer's disease : JAD
Alzheimer's disease (AD) is characterized by the presence of intracellular neurofibrillary tangles (NFT), extracellular senile plaques (SP), and synaptic loss. The hippocampus is a region that plays an important role in memory and cognitive function, and it is severely affected in AD. The levels of proteins in the hippocampus may provide a better understanding of the pathological changes known. In the present study we used two-dimensional gel electrophoresis and mass spectrometry techniques to determine changes in protein levels in AD and control hippocampus. We identified 18 proteins with altered protein levels that are involved in regulating different cellular functions. Protein levels were found to be significantly decreased for peptidyl prolyl cis/trans-isomerase (Pin 1) (0.6-fold compared to control, p<0.03), dihydropyrimidinase-like protein 2 (DRP-2) (0.74-fold compared to control, p<0.02), phosphoglycerate mutase 1 (PGM1) (0.7-fold compared to control, p<0.01), beta-tubulin (0.34-fold compared to control, p<0.01), and aldolase A (0.87-fold compared to control, p<0.0002), whereas the protein levels were found to be significantly increased for enolase (1.35-fold compared to control, p<0.05), ubiquitin carboxyl terminal hydrolase L-1 (UCH L1) (1.31-fold compared to control, p<0.02), triosephosphate isomerase (TPI) (1.38-fold compared to control, p<0.05), carbonic anhydrase II (CAH-II) (1.24-fold compared to control, p=0.05), heat shock protein 70 (1.14-fold compared to control, p<0.03), fructose bisphosphate aldolase (1.38-fold compared to control, p<0.05), ferritin heavy chain (1.23-fold compared to control, p=0.05), 2',3'-cyclic nucleotide 3' phosphodiestrase (CNPase) (1.12-fold compared to control, p<0.02), peroxiredoxin II (1.39-fold compared to control, p<0.05), and adenylate kinase I (1.19-fold compared to control, p<0.03). We found 2 proteins spots that were identified as glyceraldehyde 3-phosphate dehydrogenase (GAPDH). One of the spots showed a 1.28-fold increase in protein level compared to control (p<0.01), and the other spot showed a similar 1.26-fold increase in protein level compared to control (p<0.04). Thus, proteomics has provided knowledge of the levels of key proteins in AD brain. We discuss the functions regulated by these proteins with respect to AD pathology.
10.3233/jad-2007-11203
Identification of polypeptides in neurofibrillary tangles and total homogenates of brains with Alzheimer's disease by tandem mass spectrometry.
Minjarez Benito,Valero Rustarazo María Luz,Sanchez del Pino Manuel M,González-Robles Arturo,Sosa-Melgarejo Jorge A,Luna-Muñoz Jose,Mena Raul,Luna-Arias Juan Pedro
Journal of Alzheimer's disease : JAD
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD brains are characterized by the presence of neurofibrillary tangles (NFTs) and neuritic plaques. NFTs are constituted of paired helical filaments, which are structurally composed by assembled hyperphosphorylated and truncated tau polypeptides. To date, the integral constituents of NFTs remain unknown mainly due to the high insolubility of NFTs. The aim of this study was to identify by tandem mass spectrometry, the polypeptides contained in both isolated NFTs by laser capture microdissection and total homogenates, using tissue sections from paraformaldehyde-fixed AD brains. In the first case, we isolated 2,000 NFTs from tissue samples of hippocampus from each of the three Mexican AD brains used in our study. These were previously stained with anti-hyperphosphorylated tau AT-100 antibodies. After the removal of paraformaldehyde and delipidation with organic solvents, we tested three solubilization methods. We identified 102 polypeptides from total homogenates and 41 from isolated NFTs. We selected UCH-L1, transferrin, and GAPDH polypeptides to be studied by immunofluorescence and confocal microscopy. Only UCH-L1 and GAPDH colocalized with hyperphosphorylated tau in NFTs.
10.3233/JAD-121480
Housekeepers for accurate transcript expression analysis in Alzheimer's disease autopsy brain tissue.
Gebhardt Florian M,Scott Heather A,Dodd Peter R
Alzheimer's & dementia : the journal of the Alzheimer's Association
BACKGROUND:Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) is a popular technique for mRNA expression studies. Normalization to an endogenous reference transcript (housekeeper) is widely used to correct for differences in loading and RNA quality. Alzheimer's disease (AD) alters brain metabolism. The stability of housekeeper transcript expression must be carefully validated. METHODS:qRT-PCR was used to assess eight putative housekeeper transcripts in four brain regions from 15 control, 12 AD, and 10 AD/Lewy body disease (LBD) cases. RESULTS:RNA quality is lower in AD and AD/LBD than in controls. Frequently used housekeepers such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin had lower overall expression in AD and AD/LBD cases than in controls. RPL13 and 18S were the most stably expressed housekeepers tested. Synaptophysin and glial fibrillary acidic protein were used to evaluate normalized quantification. By using different housekeepers we confirmed that synaptophysin expression was down-regulated in AD cases, whereas glial fibrillary acidic protein expression was increased. CONCLUSIONS:Among all candidates tested, RPL13 was the best housekeeper for qRT-PCR studies in autopsy brain tissue samples from controls and AD cases. RNA quality should be assessed and data normalized on this index as well.
10.1016/j.jalz.2009.11.002
Selection of appropriate reference genes for RT-qPCR analysis in a streptozotocin-induced Alzheimer's disease model of cynomolgus monkeys (Macaca fascicularis).
Park Sang-Je,Kim Young-Hyun,Lee Youngjeon,Kim Kyoung-Min,Kim Heui-Soo,Lee Sang-Rae,Kim Sun-Uk,Kim Sang-Hyun,Kim Ji-Su,Jeong Kang-Jin,Lee Kyoung-Min,Huh Jae-Won,Chang Kyu-Tae
PloS one
Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) has been widely used to quantify relative gene expression because of the specificity, sensitivity, and accuracy of this technique. In order to obtain reliable gene expression data from RT-qPCR experiments, it is important to utilize optimal reference genes for the normalization of target gene expression under varied experimental conditions. Previously, we developed and validated a novel icv-STZ cynomolgus monkey model for Alzheimer's disease (AD) research. However, in order to enhance the reliability of this disease model, appropriate reference genes must be selected to allow meaningful analysis of the gene expression levels in the icv-STZ cynomolgus monkey brain. In this study, we assessed the expression stability of 9 candidate reference genes in 2 matched-pair brain samples (5 regions) of control cynomolgus monkeys and those who had received intracerebroventricular injection of streptozotocin (icv-STZ). Three well-known analytical programs geNorm, NormFinder, and BestKeeper were used to choose the suitable reference genes from the total sample group, control group, and icv-STZ group. Combination analysis of the 3 different programs clearly indicated that the ideal reference genes are RPS19 and YWHAZ in the total sample group, GAPDH and RPS19 in the control group, and ACTB and GAPDH in the icv-STZ group. Additionally, we validated the normalization accuracy of the most appropriate reference genes (RPS19 and YWHAZ) by comparison with the least stable gene (TBP) using quantification of the APP and MAPT genes in the total sample group. To the best of our knowledge, this research is the first study to identify and validate the appropriate reference genes in cynomolgus monkey brains. These findings provide useful information for future studies involving the expression of target genes in the cynomolgus monkey.
10.1371/journal.pone.0056034
Amyloid-beta induces disulfide bonding and aggregation of GAPDH in Alzheimer's disease.
Cumming Robert C,Schubert David
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
GAPDH is a redox-sensitive glycolytic enzyme that also promotes apoptosis when translocated to the nucleus and associates with aggregate-prone proteins involved in neurodegenerative disorders. Recent evidence indicates that polymorphic variation within GAPDH genes is associated with an elevated risk of developing Alzheimer's disease (AD). We previously demonstrated that GAPDH readily undergoes disulfide bonding following oxidant exposure, although the consequence of disulfide bonding on GAPDH activity or function is unknown. Here we show that increased GAPDH disulfide bonding is observed in detergent-insoluble extracts from AD patient and transgenic AD mouse brain tissue compared with age-matched controls. Exposure of primary rat cortical neurons to the pro-oxidant amyloid beta peptide promotes nuclear accumulation of a disulfide-linked form of GAPDH, which becomes detergent-insoluble. Disulfide bonding leads to a reduction in GAPDH enzymatic activity and correlates with the appearance of punctate aggregate-like GAPDH staining within the cytoplasm of both oxidant-treated HT22 cells and amyloid beta-treated primary cortical neurons. Our findings suggest that disulfide bonding of GAPDH and subsequent protein aggregate formation may have relevance to the pathophysiology of AD.
10.1096/fj.05-4195fje
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease.
El Kadmiri N,Slassi I,El Moutawakil B,Nadifi S,Tadevosyan A,Hachem A,Soukri A
Pathologie-biologie
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a ubiquitous enzyme that catalyzes the sixth step of glycolysis and thus, serves to break down glucose for energy production. Beyond the traditional aerobic metabolism of glucose, recent studies have highlighted additional roles played by GAPDH in non-metabolic processes, such as control of gene expression and redox post-translational modifications. Neuroproteomics have revealed high affinity interactions between GAPDH and Alzheimer's disease-associated proteins, including the β-amyloid, β-amyloid precursor protein and tau. This neuronal protein interaction may lead to impairment of the GAPDH glycolytic function in Alzheimer's disease and may be a forerunner of its participation in apoptosis. The present review examines the crucial implication of GAPDH in neurodegenerative processes and clarifies its role in apoptotic cell death.
10.1016/j.patbio.2014.08.002
An investigation of the correlation between the S-glutathionylated GAPDH levels in blood and Alzheimer's disease progression.
Tsai Chen Wei,Tsai Chia Fan,Lin Kuan Hung,Chen Wei Jung,Lin Muh Shi,Hsieh Cho Chen,Lin Chai Ching
PloS one
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by two aggregates, namely, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein (tau-p), which are released into the blood in a very small amount and cannot be easily detected. An increasing number of recent studies have suggested that S-glutathionylated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is highly correlated with Aβ in patients with AD and that S-glutathionylated GAPDH plays a role as a proapoptotic factor in AD. We found that S-glutathionylated GAPDH is abundant in the blood of AD patients, which is unusual because S-glutathionylated GAPDH cannot exist in the blood under normal conditions. The aim of this study was to further explore the correlation between the S-glutathionylated GAPDH levels in blood plasma and AD progression. As controls, we recruited 191 people without AD, which included 111 healthy individuals and 37 patients with depression and insomnia, in the psychosomatic clinic. Moreover, 47 patients with AD (aged 40-89 years) were recruited at the neurology clinic. The blood S-glutathionylated GAPDH levels in the AD patients were significantly (p < 0.001) higher (752.7 ± 301.7 ng/dL) than those in the controls (59.92 ± 122.4 ng/dL), irrespective of gender and age. For AD diagnosis, the criterion blood S-glutathionylated GAPDH level > 251.62 ng/dL exhibited 95.74% sensitivity and 92.67% specificity. In fact, the individuals aged 70-89 years, namely, 37 patients from the psychosomatic clinic and 42 healthy individuals, showed significant blood S-glutathionylated GAPDH levels (230.5 ± 79.3 and 8.05 ± 20.51 ng/dL, respectively). This finding might indicate neurodegenerative AD progression in psychosomatic patients and suggests that the degree of neuronal apoptosis during AD progression might be sensitively evaluated based on the level of S-glutathionylated GAPDH in blood.
10.1371/journal.pone.0233289
Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease.
Itakura Masanori,Nakajima Hidemitsu,Kubo Takeya,Semi Yuko,Kume Satoshi,Higashida Shusaku,Kaneshige Akihiro,Kuwamura Mitsuru,Harada Naoki,Kita Akinori,Azuma Yasu-Taka,Yamaji Ryoichi,Inui Takashi,Takeuchi Tadayoshi
The Journal of biological chemistry
Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by loss of neurons and formation of pathological extracellular deposits induced by amyloid-β peptide (Aβ). Numerous studies have established Aβ amyloidogenesis as a hallmark of AD pathogenesis, particularly with respect to mitochondrial dysfunction. We have previously shown that glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forms amyloid-like aggregates upon exposure to oxidative stress and that these aggregates contribute to neuronal cell death. Here, we report that GAPDH aggregates accelerate Aβ amyloidogenesis and subsequent neuronal cell death both in vitro and in vivo. Co-incubation of Aβ40 with small amounts of GAPDH aggregates significantly enhanced Aβ40 amyloidogenesis, as assessed by in vitro thioflavin-T assays. Similarly, structural analyses using Congo red staining, circular dichroism, and atomic force microscopy revealed that GAPDH aggregates induced Aβ40 amyloidogenesis. In PC12 cells, GAPDH aggregates augmented Aβ40-induced cell death, concomitant with disruption of mitochondrial membrane potential. Furthermore, mice injected intracerebroventricularly with Aβ40 co-incubated with GAPDH aggregates exhibited Aβ40-induced pyramidal cell death and gliosis in the hippocampal CA3 region. These observations were accompanied by nuclear translocation of apoptosis-inducing factor and cytosolic release of cytochrome c from mitochondria. Finally, in the 3×Tg-AD mouse model of AD, GAPDH/Aβ co-aggregation and mitochondrial dysfunction were consistently detected in an age-dependent manner, and Aβ aggregate formation was attenuated by GAPDH siRNA treatment. Thus, this study suggests that GAPDH aggregates accelerate Aβ amyloidogenesis, subsequently leading to mitochondrial dysfunction and neuronal cell death in the pathogenesis of AD.
10.1074/jbc.M115.669291
A proteomic approach for the involvement of the GAPDH in Alzheimer disease in the blood of Moroccan FAD cases.
El Kadmiri Nadia,Cuardos Raquel,El Moutawakil Bouchra,Slassi Ilham,Avila Jesus,Nadifi Sellama,Hachem Ahmed,Soukri Abdelaziz
Journal of molecular neuroscience : MN
Several articles have highlighted the potential involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in neurodegeneration by showing a non-glycolytic activity of GAPDH specifically in the brains of subjects with Alzheimer's disease (AD). The novel aim of this study was to elucidate the critical role of GAPDH and its interaction with β-amyloid in the blood of Moroccan patients with familial AD (FAD) carrying presenilin mutations and in sporadic late onset AD (LOAD). Our results show a significant decrease in the activity of GAPDH in blood samples from patients with FAD as compared to sporadic cases and healthy controls. The expression level of GAPDH in brain specimens from mutant tau transgenic mice and patients with FAD was unchanged as compared to healthy controls. In contrast, the expression level of GAPDH in blood samples from mutant tau transgenic mice and patients with FAD was decreased as compared to sporadic cases and healthy controls. Moreover, there is an accumulation of β-amyloid aggregates in the blood samples of patients with FAD and an increase in amyloid fibrils in both the blood and brain samples of these patients. Our study adds new insight to previous ones by showing the involvement of GAPDH in AD, which may influence the pathogenesis of this neurodegenerative disease.
10.1007/s12031-014-0374-8