The systematic molecular associations between the peripheral blood cells and brain in Alzheimer's disease (AD) remains unclear, which hinders our understanding of AD pathological mechanisms and the ...exploration of new diagnostic biomarkers.
Here, we performed an integrated analysis of the brain and peripheral blood cells transcriptomics to establish peripheral biomarkers of AD. By employing multiple statistical analyses plus machine learning, we identified and validated multiple regulated central and peripheral network in patients with AD.
By bioinformatics analysis, a total of 243 genes were differentially expressed in the central and peripheral systems, mainly enriched in three modules: immune response, glucose metabolism and lysosome. In addition, lysosome related gene ATP6V1E1 and immune response related genes (IL2RG, OSM, EVI2B TNFRSF1A, CXCR4, STAT5A) were significantly correlated with Aβ or Tau pathology. Finally, receiver operating characteristic (ROC) analysis revealed that ATP6V1E1 showed high-diagnostic potential for AD.
Taken together, our data identified the main pathological pathways in AD progression, particularly the systemic dysregulation of the immune response, and provided peripheral biomarkers for AD diagnosis.
Background
Olfactory dysfunction is known to be an early manifestation of Alzheimer's disease (AD). However, the underlying mechanism, particularly the specific molecular events that occur during the ...early stages of olfactory disorders, remains unclear.
Methods
In this study, we utilized transcriptomic sequencing, bioinformatics analysis, and biochemical detection to investigate the specific pathological and molecular characteristics of the olfactory bulb (OB) in 4‐month‐old male triple transgenic 3xTg‐AD mice (PS1M146V/APPSwe/TauP301L).
Results
Initially, during the early stages of olfactory impairment, no significant learning and memory deficits were observed. Correspondingly, we observed significant accumulation of amyloid‐beta (Aβ) and Tau pathology specifically in the OB, but not in the hippocampus. In addition, significant axonal morphological defects were detected in the olfactory bulb, cortex, and hippocampal brain regions of 3xTg‐AD mice. Transcriptomic analysis revealed a significant increase in the expression of neuroinflammation‐related genes, accompanied by a significant decrease in neuronal activity‐related genes in the OB. Moreover, immunofluorescence and immunoblotting demonstrated an activation of glial cell biomarkers Iba1 and GFAP, along with a reduction in the expression levels of neuronal activity‐related molecules Nr4a2 and FosB, as well as olfaction‐related marker OMP.
Conclusion
In sum, the early accumulation of Aβ and Tau pathology induces neuroinflammation, which subsequently leads to a decrease in neuronal activity within the OB, causing axonal transport deficits that contribute to olfactory disorders. Nr4a2 and FosB appear to be promising targets for intervention aimed at improving early olfactory impairment in AD.
The early accumulation of Aβ and Tau pathology induces neuroinflammation, which subsequently leads to a decrease in neuronal activity within the OB, causing axonal transport deficits that contribute to olfactory disorders. Nr4a2 and FosB appear to be promising targets for intervention aimed at improving early olfactory impairment in AD.
Hyperhomocysteinemia (Hhcy) may induce memory deficits with β‐amyloid (Aβ) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma ...homocysteine level and attenuated tau hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer‐like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2‐week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy‐induced memory deficits, enhance long‐term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up‐regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy‐induced tau hyperphosphorylation at multiple AD‐related sites through activation protein phosphatase‐2A (PP2A) with decreased inhibitory demethylated PP2AC at Leu309 and phosphorylated PP2AC at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin‐1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy‐induced AD‐like pathological changes and memory deficits.
We have found that betaine can attenuate Hcy‐induced spatial memory deficits with possible mechanisms that may involve in the expresions or/and activations of several memory‐related proteins, and increase the dendritic branches and spine density in hippocampal CA1 region. It also attenuated AD‐like tau hyperphosphorylation by activation PP2A, and inhibited Aβ aggregation by decreasing PS‐1.
Accumulation of microtubule-associated protein tau has been observed in the brain of aging and tauopathies. Tau was observed in microglia, but its role is not illustrated. By immunofluorescence ...staining and the fractal dimension value assay in the present study, we observed that microglia were activated in the brains of rats and mice during aging, simultaneously, the immunoreactivities of total tau and the phosphorylated tau were significantly enhanced in the activated microglia. Furtherly by transient transfection of tau40 (human 2N/4R tau) into the cultured rat microglia, we demonstrated that expression of tau40 increased the level of Iba1, indicating activation of microglia. Moreover, expression of tau40 significantly enhanced the membranous localization of the phosphorylated tau at Ser396 in microglia possibly by a mechanism involving protein phosphatase 2A, extracellular signal-regulated kinase and glycogen synthase kinase-3β. It was also found that expression of tau40 promoted microglial migration and phagocytosis, but not proliferation. And we observed increased secretion of several cytokines, including interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α and nitric oxide after the expression of tau40. These data suggest a novel role of human 2N/4R tau in microglial activation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The impairment of histone acetylation is causally linked to the cognitive decline in Alzheimer's disease (AD). In addition to histone acetyltransferases (HATs) and histone deacetylases (HDACs), ...inhibitor of acetyltransferases (INHAT) can also regulate histone acetylation. As a key component of INHAT, level of ANP32A is selectively upregulated in the brain of AD patients. Here we investigated whether downregulating ANP32A can rescue AD-like synapse and memory deficits.
RFP-labeled lentiviral ANP32A-shRNA was infused stereotaxically into the hippocampal CA3 region of the human tau transgenic mice (termed htau). The spatial learning and memory were assessed by Morris water maze (MWM). The synaptic function was measured by electrophysiological recording and the spine density was detected by Golgi staining. RT-PCR and Western blotting were used to detect the mRNA and protein levels.
Elevation of ANP32 in htau transgenic mice was correlated with learning deficits, while the hippocampal infusion of lenti-siANP32A to downregulate ANP32A in 12 m-old htau mice could rescue memory loss. Further studies demonstrated that downregulating ANP32A restored synapse morphology and the function. In the brain of htau mice, the acetylated histone decreased while knockdown ANP32A unmasked histone for a robust acetylation with reduced INHAT complex formation. Downregulating of ANP32A also attenuated AD-like tau hyperphosphorylation. Finally, several AD-associated risk factors, including tau accumulation, β-amyloid and H
O
exposure, increased ANP32A by activating CCAAT/enhancer binding protein-β (C/EBPβ).
We conclude that downregulating ANP32A rescues synaptic plasticity and memory ability by reducing INHAT formation and unmasking histone for hyperacetylation. Our findings reveal novel mechanisms for AD memory loss and potential molecular markers for protection.
Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer's disease. Enhancing adult hippocampal neurogenesis has been pursued as a potential therapeutic strategy for ...Alzheimer's disease. Recent studies have demonstrated that environmental novelty activates β
-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β
-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer's disease. To test this hypothesis, we investigated the effects and mechanisms of action of β
-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 (APP/PS1) mice using the agonist clenbuterol (intraperitoneal injection, 2 mg/kg). We found that β
-adrenoceptor activation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines. These effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β
-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β
-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS1 mice.
There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of ...acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer's disease.
Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. ...However, the mechanism（s） by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study,we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1-42. HN also attenuated Aβ1-42-induced tau hyperphosphorylation,apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A（PP2A）catalytic subunit and thereby activating PP2 A. HN also inhibited apoptosis and reduced the oxidativestress induced by Aβ1-42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1-42-induced AD-like pathological changes and memory deficits.
Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement ‘blood’ and ‘qi’ (vital ...energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear.
This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD).
The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification.
In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aβ accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters.
These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.
Treated by DBD, the level of phosphorylation of APP was downregulated to cause Aβ deposition to decrease in APP/PS1 mice. Meanwhile, DBD restored mitochondrial biogenesis by the HDAC2/H4K12 acetylation/PGC-1α pathway and improved synaptic plasticity through the HDAC2/H4K12 acetylation/GluN2B pathway. In conclusion, DBD could ameliorate cognitive deficits in APP/PS1 mice. Display omitted
•DBD ameliorated cognitive deficits in APP/PS1 mice.•DBD attenuated Aβ deposition by decreasing the phosphorylation of APP at the Thr668 level.•DBD restored mitochondrial biogenesis by the HDAC2/H4K12 acetylation/PGC-1α pathway.•DBD improved synaptic plasticity through the HDAC2/H4K12 acetylation/GluN2B pathway.
Aging is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease, however, aging people are not all destined to develop into cognitive deficits, the molecular ...mechanisms underlying this difference in cognition of aging people are obscure. Epigenetic modifications, particularly histone acetylation in the nervous system, play a critical role in regulation of gene expression for learning and memory. An inhibitor of acetyltransferases (INHAT) is reported to suppress histone acetylation via a histone-masking mechanism, and pp32 is a key component of INHAT complex. In the present study, we divided ~18 m-old aged mice into the cognitive-normal and the cognitive-impaired group by Morris water maze, and found that pp32 level was significantly increased in the hippocampus of cognitive-impaired aged mice. The mRNA and protein levels of synaptic-associated proteins decreased with reduced dendrite complexity and histone acetylation. Knockdown of pp32 rescued cognitive decline in cognitive-impaired aged mice with restoration of synaptic-associated proteins, the increase of spine density and elevation of histone acetylation. Our study reveals a novel mechanism underlying the aging-associated cognitive disturbance, indicating that suppression of pp32 might represent a promising therapeutic approach for learning and memory impairments.
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