Alzheimer's Disease Hippocampus Research Articles

The effect of beta-amyloid and tau protein aggregations on magnetic susceptibility of anterior hippocampal laminae in Alzheimer's diseases

Previous studies have reported the changes of magnetic susceptibility induced by iron deposition in hippocampus of Alzheimer's disease (AD) brains. It is well-known that hippocampus is divided into well-defined laminar architecture, which, however, is difficult to be resolved with in-vivo MRI due to the limited imaging resolution. The present study aims to investigate layer-specific magnetic susceptibility in the hippocampus of AD patients using high-resolution ex-vivo MRI, and elucidate its relationship with beta amyloid (Aβ) and tau protein histology. We performed quantitative susceptibility mapping (QSM) and T2* mapping on postmortem anterior hippocampus samples from four AD, four Primary Age-Related Tauopathy (PART), and three control brains. We manually segmented each sample into seven layers, including four layers in the cornu ammonis1 (CA1) and three layers in the dentate gyrus (DG), and then evaluated AD-related alterations of susceptibility and T2* values and their correlations with Aβ and tau in each hippocampal layer. Specifically, we found (1) layer-specific variations of susceptibility and T2* measurements in all samples; (2) the heterogeneity of susceptibility were higher in all layers of AD patients compared with the age- and gender-matched PART cases while the heterogeneity of T2* values were lower in four layers of CA1; and (3) voxel-wise MRI-histological correlation revealed both susceptibility and T2* values in the stratum molecular (SM) and stratum lacunosum (SL) layers were correlated with the Aβ content in AD, while the T2* values in the stratum radiatum (SR) layer were correlated with the tau content in the PART but not AD. These findings suggest a selective effect of the Aβ- and tau-pathology on the susceptibility and T2* values in the different layers of anterior hippocampus. Particularly, the alterations of magnetic susceptibility in the SM and SL layers may be associated with Aβ aggregation, while those in the SR layermay reflect the age-related tau protein aggregation.

The effect of vitamin B12 on synaptic plasticity of hippocampus in Alzheimer’s disease model rats

Background Hippocampus cells, responsible for learning and memory, are disturbed in Alzheimer’s disease (AD), resulting in production of several inflammatory markers, such as neurexin 1 –neuroligin, cyclooxygenase–2 (COX–2), and caspase–3 proteins, used in measurement of AD’s severity and development. Vitamin B12, which plays a role in brain functioning, has anti–inflammatory properties and its impairment is associated with apoptosis in Alzheimer’s disease. This study aimed to investigate the effect of vitamin B12 on restoration of Synaptic Plasticity on scopolamine–induced AD in rats. Methods To simulate AD, Rats, except the control group were i.p. injected with 3 mg/kg scopolamine. Before scopolamine the pretreatment group vitamin B12 (0.5, 2, and 4 mg/kg) was injected every day for the next 14 days. After 24 h, sectioning the rats’ brains, the concentration of postsynaptic density protein 95 (PSD–95), neurexin 1–neurolgin, COX–2, and caspase–3 proteins in hippocampus were measured using immunoblotting. Results B12 significantly enhanced molecular balance. PSD–95 and neurexin 1 and neuroligin concentrations were significantly reduced, whereas COX–2 and activated caspase–3 were enhanced in the hippocampus of scopolamine–injected subjects. Their alterations were decreased after B12 administration. Conclusions Vitamin B12 protected scopolamine–injected rats and inhibited hippocampal inflammation and apoptosis and preserved pre– and post–synaptic proteins and possibly synaptic integrity in hippocampus route.

The Effects Of Long-term Treadmill Running Exercise On Nek7 Expression In Hippocampus Of AD Model Mouse

PURPOSE: The effects of treadmill running for 20 weeks intervention on the memory abilities and the expression of NEK7, IL-1β and IL-10 in hippocampus of Alzheimer's disease (AD) model mouse. METHODS: Twenty male APP/PS1 (three months old) mouse (C57BL/6JNju) were randomly divided into two groups: AD control group (AC, n = 10) and AD exercise group (AE, n = 10). Following acclimation to laboratory conditions for one week. The AE group was intervened by treadmill exercise for 20 weeks (12 m/min, 30 min/day, 5 days/week), the AC group was normally fed for 20 weeks. The Morris water maze experiment lasted for one week at week 20, to evaluate the spatial learning and memory function of the mice. Then brain tissue was taken, immunofluorescence was used to detect IL-1β and IL-10 deposition, and Western Blot were used to detect NEK7 deposition in hippocampus of mouse. The experimental data was reported as mean ± SE, and processed with one-way ANOVA, level of significance was set at α = 0.05. RESULTS: (1) Water maze navigation trial showed that the average escape latency of each group showed a downward trend. Compared with AC group, the decreasing trend of AE group was more significant. In the space exploration experiment, the average frequency of crossing the platform in AC group were significantly less than those in AE group (P < 0.01, AC = 1.48 ± 0.89, AE = 3.89 ± 1.20). (2) Immunofluorescence showed that the expression level of IL-1β of AE group was significantly lower than that of AC group(P < 0.01), but IL-10 of AE group was significantly higher than that of AC group (P < 0.01) in the hippocampus. (3) Western blot results showed that NEK7 expression level in AE group was significantly lower than that in AC group (P < 0.01, AC = 0.45 ± 0.02, AE = 0.19 ± 0.03). CONCLUSION: Long-term treadmill running exercise can improve the spatial learning and memory function of AD model mice. The mechanism may be due to inhibition Nek7 protein, thus inhibition IL-1β, promotion the expression of IL-10. These results indicate that long-term treadmill running exercise alleviation brain inflammation and prevent the impairment of spatial learning and memory function of AD.

Genetic Exchange of Lung-Derived Exosome to Brain Causing Neuronal Changes on COVID-19 Infection.

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2–infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2–infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson’s disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer’s disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-021-02485-9.

G protein-coupled receptor kinases are associated with Alzheimer's disease pathology.

Alzheimer's disease (AD) is characterised by extracellular deposition of amyloid-β (Aβ) in amyloid plaques and intracellular aggregation and accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs). Although several kinases have been identified to contribute to the pathological phosphorylation of tau, kinase-targeted therapies for AD have not been successful in clinical trials. Critically, the kinases responsible for numerous identified tau phosphorylation sites remain unknown. G protein-coupled receptor (GPCR) kinases (GRKs) have recently been implicated in phosphorylation of non-GPCR substrates, for example, tubulin and α-synuclein, and in neurological disorders, including schizophrenia and Parkinson's disease. Accordingly, we investigated the involvement of GRKs in the pathophysiology of AD. We performed a comprehensive immunohistochemical and biochemical analysis of the ubiquitously expressed GRKs, namely, GRK2, 3, 5 and 6, in postmortem human brain tissue of control subjects and AD patients. GRKs display unique cell-type-specific expression patterns in neurons, astrocytes and microglia. Levels of GRKs 2, 5 and 6 are specifically decreased in the CA1 region of the AD hippocampus. Biochemical evidence indicates that the GRKs differentially associate with total, soluble and insoluble pools of tau in the AD brain. Complementary immunohistochemical studies indicate that the GRKs differentially colocalise with total tau, phosphorylated tau and NFTs. Notably, GRKs 3 and 5 also colocalise with amyloid plaques. These studies establish a link between GRKs and the pathological phosphorylation and accumulation of tau and amyloid pathology in AD brains and suggest a novel role for these kinases in regulation of the pathological hallmarks of AD.

Glutamatergic receptor expression changes in the Alzheimer's disease hippocampus and entorhinal cortex.

Alzheimer's Disease (AD) is the leading form of dementia worldwide. Currently, the pathological mechanisms underlying AD are not well understood. Although the glutamatergic system is extensively implicated in its pathophysiology, there is a gap in knowledge regarding the expression of glutamate receptors in the AD brain. This study aimed to characterize the expression of specific glutamate receptor subunits in post‐mortem human brain tissue using immunohistochemistry and confocal microscopy. Free‐floating immunohistochemistry and confocal laser scanning microscopy were used to quantify the density of glutamate receptor subunits GluA2, GluN1, and GluN2A in specific cell layers of the hippocampal sub‐regions, subiculum, entorhinal cortex, and superior temporal gyrus. Quantification of GluA2 expression in human post‐mortem hippocampus revealed a significant increase in the stratum (str.) moleculare of the dentate gyrus (DG) in AD compared with control. Increased GluN1 receptor expression was found in the str. moleculare and hilus of the DG, str. oriens of the CA2 and CA3, str. pyramidale of the CA2, and str. radiatum of the CA1, CA2, and CA3 subregions and the entorhinal cortex. GluN2A expression was significantly increased in AD compared with control in the str. oriens, str. pyramidale, and str. radiatum of the CA1 subregion. These findings indicate that the expression of glutamatergic receptor subunits shows brain region‐specific changes in AD, suggesting possible pathological receptor functioning. These results provide evidence of specific glutamatergic receptor subunit changes in the AD hippocampus and entorhinal cortex, indicating the requirement for further research to elucidate the pathophysiological mechanisms it entails, and further highlight the potential of glutamatergic receptor subunits as therapeutic targets.

Bioinformatics analysis of differentially expressed genes and identification of an miRNA\u2013mRNA network associated with entorhinal cortex and hippocampus in Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is a fatal neurodegenerative disorder, and the lesions originate in the entorhinal cortex (EC) and hippocampus (HIP) at the early stage of AD progression. Gaining insight into the molecular mechanisms underlying AD is critical for the diagnosis and treatment of this disorder. Recent discoveries have uncovered the essential roles of microRNAs (miRNAs) in aging and have identified the potential of miRNAs serving as biomarkers in AD diagnosis.MethodsWe sought to apply bioinformatics tools to investigate microarray profiles and characterize differentially expressed genes (DEGs) in both EC and HIP and identify specific candidate genes and pathways that might be implicated in AD for further analysis. Furthermore, we considered that DEGs might be dysregulated by miRNAs. Therefore, we investigated patients with AD and healthy controls by studying the gene profiling of their brain and blood samples to identify AD-related DEGs, differentially expressed miRNAs (DEmiRNAs), along with gene ontology (GO) analysis, KEGG pathway analysis, and construction of an AD-specific miRNA–mRNA interaction network.ResultsOur analysis identified 10 key hub genes in the EC and HIP of patients with AD, and these hub genes were focused on energy metabolism, suggesting that metabolic dyshomeostasis contributed to the progression of the early AD pathology. Moreover, after the construction of an miRNA–mRNA network, we identified 9 blood-related DEmiRNAs, which regulated 10 target genes in the KEGG pathway.ConclusionsOur findings indicated these DEmiRNAs having the potential to act as diagnostic biomarkers at an early stage of AD.

Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation.

Repair after traumatic injury often starts with mitotic activation around the lesion edges. Early midline cells in the Drosophila embryonic CNS can enter into division following the traumatic disruption of microtubules. We demonstrate that microtubule disruption activates non-canonical TNF signaling by phosphorylation of TGF-β activated kinase 1 (Tak1) and its target IkappaB kinase (Ik2), culminating in Dorsal/NfkappaB nuclear translocation and Jra/Jun expression. Tak1 and Ik2 are necessary for the damaged-induced divisions. Microtubule disruption caused by Tau accumulation is also reported in Alzheimer's disease (AD). Human Tau expression in Drosophila midline cells is sufficient to induce Tak1 phosphorylation, Dorsal and Jra/Jun expression, and entry into mitosis. Interestingly, activation of Tak1 and Tank binding kinase 1 (Tbk1), the human Ik2 ortholog, and NfkappaB upregulation are observed in AD brains.

ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer's disease

Although the exact etiology of Alzheimer's disease (AD) is poorly understood, experimental and clinical evidences suggest the contribution of neuroinflammation in the pathogenesis of AD. Pathologically, AD brain is characterized by an imbalance in redox status, elevated endoplasmic reticulum (ER) stress, synaptic dysfunction, inflammation, and progressive neurodegeneration. It has been noted that continuous accumulation of amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFTs) in AD brain trigger ER stress, which contributes to neurodegeneration. Similarly, experimental evidences supports the hypothesis that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox regulator thioredoxin (TRX), is activated by ER stress and contributes to activation of NLRP3 (NOD-like receptor protein 3) inflammatory cascade in hippocampus of the AD brain. Hippocampus of postmortem human AD and aged matched non-AD controls were analyzed for the expression ER stress markers and TXNIP-NLRP3 inflammasome at cellular and molecular levels. We found higher expression of TXNIP at protein and transcript levels in close association with pathological markers of AD such as Aβ and NFTs in AD hippocampus. In addition, our results demonstrated that TXNIP was co-localized in neurons and microglia. Moreover, expression of binding immunoglobulin protein (BiP), activated eukaryotic initiation factor-2α (eIf2α) and C/EBP homology protein (CHOP), proteins involved the development of ER stress, were elevated in AD hippocampus. Further, elevated expression of effector molecules of NLRP3 inflammasome activation such as apoptosis associated speck-like protein (ASC), cleaved caspase-1 and cleaved interleukin-1β were observed in the AD hippocampus. The study suggests that TXNIP could be a link that connect ER stress with neuroinflammation. Thus, TXNIP can be a possible therapeutic target to mitigate the progression of neuroinflammation in the pathogenesis of AD.

Partial volume correction analysis for 11C-UCB-J PET studies of Alzheimer's disease

Purpose11C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC). MethodsWe performed two PVC algorithms, Müller-Gärtner (MG) and ‘iterative Yang’ (IY), on 17 AD participants and 11 cognitive normal (CN) participants using the brain-dedicated HRRT scanner. Distribution volume VT, the rate constant K1, binding potential BPND (centrum semiovale as reference region), and tissue volume were compared. ResultsIn most regions, both PVC algorithms reduced the between-group differences. Alternatively, in hippocampus, IY increased the significance of between-group differences while MG reduced it (VT, BPND and K1 group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions. Conclusion11C-UCB-J binding is significantly reduced in AD hippocampus, but PVC is important to adjust for significant volume reduction. After correction, PET measures are substantially more sensitive to group differences than volumetric MRI measures. Assumptions of each PVC algorithm are important and should be carefully examined and validated. For 11C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG.

Poria cocos polysaccharide attenuates damage of nervus in Alzheimer's disease rat model induced by D-galactose and aluminum trichloride.

Poria cocos polysaccharide (PCP) is a compound from Poria cocos, and which is used as a classical tonic agent. This article aims to investigate the effects of PCP on neuronal damage of hippocampus and cognitive function in a rat model of Alzheimer's disease induced by D-galactose and aluminum trichloride. Oxiracetam (ORC) was used as a positive drug in this experiment. The rats were treated with PCP at doses of 100, 200 and 300 mg/kg/day for 30 days and ORC at dose of 346 mg/kg/day after modeling. The results of behavioral test showed that PCP could prevent cognitive decline in Alzheimer's disease rats as assessed by Y-maze test and Morris water maze test. Results of hippocampus slices showed that neurons were integrated and regularly arranged in the groups, which were administered along with PCP. Moreover, PCP could reduce neuronal apoptosis in hippocampus of Alzheimer's disease rats. Furthermore, the activities of superoxide dismutase in the hippocampus were elevated by PCP administration, while acetyl cholinesterase, reactive oxygen, malondialdehyde and inflammatory factors levels were reduced. In addition, we found PCP could attenuate MAPK/NF-κB signal pathway in the hippocampus. All results illustrated that PCP could exert neuroprotective effects at least partly through alleviating oxidative stress, apoptosis, inflammation and inhibiting the MAPK/NF-κB pathway in Alzheimer's disease rats induced by D-galactose and aluminum trichloride.

Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer's disease.

Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer\u2019s disease

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease.

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer's disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC-NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC-NA axons coincides with the heightened β-AR function at medial perforant path-dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.SIGNIFICANCE STATEMENT The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer's disease (AD) pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β-adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.

Protein hyper‐glycosylation is a metabolic feature of mouse and human brains with beta amyloid pathology

Glycomics is the study of complex carbohydrates throughout their metabolic lifecycle; precise profiling of these oligosaccharides has been shown to provide a critical understanding of the current state of a disease. N-linked glycans are a subset of the glycome containing co-translational modifications found on cell surface, secreted, and circulating proteins. Prior research shows glycosylation perturbations in Alzheimer's disease (AD), however, these patterns have not been extensively studied in specific brain regions with underlying disease pathology. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a revolutionary technique that combines traditional mass spectrometry with high-resolution imaging to visualize microenvironmental glycan distribution. Using our improved, enzyme-assisted workflow, we can define sub-regional N-linked glycan features in multiple areas of the brain implicated in AD pathogenesis including the hippocampus and the frontal cortex. We saw a profound hyper N-linked glycosylation pattern in multiple (n=4) 5xFAD mouse model (beta-amyloid pathology) brain regions compared to age- and sex-matched, heterozygous littermate controls. Consistent with our in vivo findings, MALDI-MSI analysis of human AD hippocampus and frontal cortex tissue samples revealed a similar hyper glycosylation phenotype. Our studies suggest that beta-amyloid is a metabolic modifier of N-linked glycosylation and could be an exciting therapeutic approach as well as a potential biomarker for AD progression. In the future, we plan to use these results to further investigate specific glycosylation pathways that promote AD pathogenesis, and how these modifications contribute to ER stress and the unfolded protein response, inflammation, and neuronal cell death.

Zfra and its activated Z cell suppress traumatic brain injury to Alzheimer's disease transition

As a risk factor for Alzheimer's disease(AD), WW domain-containing oxidoreductase (WWOX) becomes phosphorylated at S14 in the lesions of AD hippocampus and cortex. It appears that the severity of AD progression is associated with pS14-WWOX accumulation. Suppression of WWOX phosphorylation at S14 and clearance of tau and amyloid beta aggregation by a 7-amino-acid zinc finger like peptide Zfra4-10 leads to restoration of memory loss in 10-month-old triple transgenic mice for AD (3xTg). Here, we test the hypothesis that transition of acute phase traumatic brain injury (TBI) to AD-like symptoms in the chronic phase correlates with a shift of pY33 to pS14 in WWOX. When BALB/c mice were subjected to TBI, these mice exhibited rapid increases in the accumulation of aggregates of amyloid beta, alpha-synuclein and neurofibrillary tangles (NFT), along with increases in the proapoptotic pY33-WWOX. Zfra significantly cleared up the protein aggregates. A novel estrogen receptor-binding protein ankyrin repeat domain 40 (ANR40) was isolated, and its phosphorylation at S154 identified. TBI upregulated ANR40 without S154 phosphorylation. In contrast, Zfra upregulated pS154-ANR40 during the acute phase of TBI followed by reduction in chronic phase, suggesting that pS154-ANR40 is neuroprotective. Additionally, Zfra-activated spleen Hyal-2+ Z cells are potent in blocking Pentylenetetrazole (PTZ)-mediated seizure in 3xTg mice. When activated Z cells were transferred to TBI-treated mice, their short-term memory during novel objective test recovered significantly. Together, transition of TBI to AD-like symptom with age in mice involves pY33-WWOX disappearance and pS14-WWOX accumulation. Both Zfra peptide and Z cells are of therapeutic value in TBI treatment.

Hypoxia compromises the mitochondrial metabolism of Alzheimer's disease microglia via HIF1.

Genetic Alzheimer's disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.

Cellular studies of the two main isoforms of human d-aspartate oxidase.

Human d-aspartate oxidase (hDASPO) is a FAD-dependent enzyme responsible for the degradation of d-aspartate (d-Asp). In the mammalian central nervous system, d-Asp behaves as a classical neurotransmitter, it is thought to be involved in neural development, brain morphology and behavior, and appears to be involved in several pathological states, such as schizophrenia and Alzheimer's disease. Apparently, the human DDO gene produces alternative transcripts encoding for three putative hDASPO isoforms, constituted by 341 (the 'canonical' form), 369, and 282 amino acids. Despite the increasing interest in hDASPO and its physiological role, little is known about these different isoforms. Here, the additional N-terminal peptide present in the hDASPO_369 isoform only has been identified in hippocampus of Alzheimer's disease female patients, while peptides corresponding to the remaining part of the protein were present in samples from male and female healthy controls and Alzheimer's disease patients. The hDASPO_369 isoform was largely expressed in E.coli as insoluble protein, hampering with its biochemical characterization. Furthermore, we generated U87 human glioblastoma cell clones stably expressing hDASPO_341 and, for the first time, hDASPO_369 isoforms; the latter protein showed a lower expression compared with the canonical isoform. Both protein isoforms are active (showing similar kinetic properties), localize to the peroxisomes, are very stable (a half-life of approximately 100h has been estimated), and are primarily degraded through the ubiquitin-proteasome system. These studies shed light on the properties of hDASPO isoforms with the final aim to clarify the mechanisms controlling brain levels of the neuromodulator d-Asp.

Beneficial consequences of probiotic on mitochondrial hippocampus in Alzheimer's disease.

Alzheimer's (AD) is one of the most common neurodegenerative diseases, causing dementia and brain cells death. This study aimed to assess the ameliorating effect ofAcidophilus probiotic against AD induced in rats by d-galactose and AlCl3 injection via evaluating mitochondrial parameter changes in hippocampus. This study was carried out on rats were classified into five groups; G1 (control group), G2 (probiotic group), G3 (AD group), G4 (co-treated group) and G5 (post-treated group). By the end of the experiment, some different neurotransmitters, oxidative stress biomarkers, zinc, blood glucose, Na+K-ATPase subunit alpha 1 (ATP1A1), and gene expression of mitochondrial membrane potential (MMP) were measured. Significant changes in neurotransmitters, antioxidants levels and decreased ATP1A1 activity and gene expression of MMP in the hippocampus in G3 were detected if compared to control. Best improvement in G5 than G4 group was observed. These results were confirmed by histological and immunohistochemical studies in hippocampus. Acidophilus probiotic was able to alleviate learning and memory associated injuries in AD by reducing mitochondrial dysfunction induced by d-galactose and AlCl3. This may be associated with its antioxidant properties.

Tau Pathology and Adult Hippocampal Neurogenesis: What Tau Mouse Models Tell us?

Adult hippocampal neurogenesis (AHN) has been widely confirmed in mammalian brains. A growing body of evidence points to the fact that AHN sustains hippocampal-dependent functions such as learning and memory. Impaired AHN has been reported in post-mortem human brain hippocampus of Alzheimer's disease (AD) and is considered to contribute to defects in learning and memory. Neurofibrillary tangles (NFTs) and amyloid plaques are the two key neuropathological hallmarks of AD. NFTs are composed of abnormal tau proteins accumulating in many brain areas during the progression of the disease, including in the hippocampus. The physiological role of tau and impact of tau pathology on AHN is still poorly understood. Modifications in AHN have also been reported in some tau transgenic and tau-deleted mouse models. We present here a brief review of advances in the relationship between development of tau pathology and AHN in AD and what insights have been gained from studies in tau mouse models.