Alzheimer's Disease Hippocampus Research Articles

Adenovirus-Mediated Transduction of Insulin-Like Growth Factor 1 Protects Hippocampal Neurons from the Toxicity of Aβ Oligomers and Prevents Memory Loss in an Alzheimer Mouse Model.

Alzheimer's disease (AD) is the main cause of dementia in the elderly. Although activation of brain insulin signaling has been shown to be neuroprotective, to preserve memory in AD models, and appears beneficial in patients, the role of insulin-like growth factor 1 (IGF1) remains incompletely understood. We found reduced active/inactive IGF1 ratio and increased IGF1R expression in postmortem hippocampal tissue from AD patients, suggesting impaired brain IGF1 signaling in AD. Active/inactive IGF-1 ratio was also reduced in the brains of mouse models of AD. We next investigated the possible protective role of IGF1 in AD models. We used a recombinant adenoviral vector, RAd-IGF1, to drive the expression of IGF1 in primary hippocampal neuronal cultures prior to exposure to AβOs, toxins that accumulate in AD brains and have been implicated in early synapse dysfunction and memory impairment. Cultures transduced with RAd-IGF1 showed decreased binding of AβOs to neurons and were protected against AβO-induced neuronal oxidative stress and loss of dendritic spines. Significantly, in vivo transduction with RAd-IGF1 blocked memory impairment caused by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Our results demonstrate altered active IGF1 and IGF1R levels in AD hippocampi, and suggest that boosting brain expression of IGF1 may comprise an approach to prevent neuronal damage and memory loss in AD.

N368-Tau fragments generated by legumain are detected only in trace amount in the insoluble Tau aggregates isolated from AD brain

Intraneuronal insoluble inclusions made of Tau protein are neuropathological hallmarks of Alzheimer Disease (AD). Cleavage of Tau by legumain (LGMN) has been proposed to be crucial for aggregation of Tau into fibrils. However, it remains unclear if LGMN-cleaved Tau fragments accumulate in AD Tau inclusions.Using an in vitro enzymatic assay and non-targeted mass spectrometry, we identified four putative LGMN cleavage sites at Tau residues N167-, N255-, N296- and N368. Cleavage at N368 generates variously sized N368-Tau fragments that are aggregation prone in the Thioflavin T assay in vitro. N368-cleaved Tau is not detected in the brain of legumain knockout mice, indicating that LGMN is required for Tau cleavage in the mouse brain in vivo. Using a targeted mass spectrometry method in combination with tissue fractionation and biochemical analysis, we investigated whether N368-cleaved Tau is differentially produced and aggregated in brain of AD patients and control subjects. In brain soluble extracts, despite reduced uncleaved Tau in AD, levels of N368-cleaved Tau are comparable in AD and control hippocampus, suggesting that LGMN-mediated cleavage of Tau is not altered in AD. Consistently, levels of activated, cleaved LGMN are also similar in AD and control brain extracts. To assess the potential accumulation of N368-cleaved Tau in insoluble Tau aggregates, we analyzed sarkosyl-insoluble extracts from AD and control hippocampus. Both N368-cleaved Tau and uncleaved Tau were significantly increased in AD as a consequence of pathological Tau inclusions accumulation. However, the amount of N368-cleaved Tau represented only a very minor component (< 0.1%) of insoluble Tau.Our data indicate that LGMN physiologically cleaves Tau in the mouse and human brain generating N368-cleaved Tau fragments, which remain largely soluble and are present only in low proportion in Tau insoluble aggregates compared to uncleaved Tau. This suggests that LGMN-cleaved Tau has limited role in the progressive accumulation of Tau inclusions in AD.

MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging/capture in an Aβ(1-42)-induced model of Alzheimer's disease.

Progressive memory loss is one of the most common characteristics of Alzheimer's disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long‐term potentiation (late LTP) and its associative mechanisms such as synaptic tagging and capture (STC) were impaired in Aβ (1–42)‐induced AD condition. This study demonstrates that expression of miR‐134‐5p, a brain‐specific miRNA is upregulated in Aβ (1–42)‐treated AD hippocampus. Interestingly, the loss of function of miR‐134‐5p restored late LTP and STC in AD. In AD brains, inhibition of miR‐134‐5p elevated the expression of plasticity‐related proteins (PRPs), cAMP‐response‐element binding protein (CREB‐1) and brain‐derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR‐134‐mediated post‐transcriptional regulation of CREB‐1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR‐134‐5p as a potential therapeutic target for restoring plasticity in AD condition.

The correlation of functional connectivity and structural connectivity between hippocampus and thalamus in Alzheimer's disease and amnestic mild cognitive impairment

Objective: To investigate the correlation of functional connectivity (FC) and the integrity of connective fibres between hippocampus and thalamus in Alzheimer's disease(AD) and amnestic mild cognitive impairment (aMCI). Methods: Both resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) data of 40 AD patients, 37 aMCI patients and 41 normal control subjects matching with age and educational level were collected. These subjects were all recruited from outpatient Department of Neurology in the Second Medical Center of Chinese PLA General Hospital, as well as poster, from May 2016 to January 2018. The FC strength between bilateral hippocampus and thalamus, as well as the parameters representing integrity of connective fibres, including fractional anisotropy (FA) and mean diffusivity(MD),were analyzed. Also, the correlations between FC strength and FA or MD strength were analyzed in the study. Results: Compared to that of normal control subjects, the FC strength between billateral hippocampus and thalamus in patients with AD, aMCI were not significantly different(P>0.05). The integrity of bilateral connective fibres between hippocampus and thalamus were damaged in AD patients when compared to normal control subjects(P<0.01). A positive correlation of connective fibres integrity with FC strength between hippocampus and thalamus was found in the left side(r=0.25,P<0.05) but rather in the right side. Conclusion: In AD and aMCI patients, structural connectivity between left hippocampus and thalamus affects the functional connectivity between them.

High-resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer's disease mice

Accumulating evidence indicates the critical importance of cerebrovascular dysfunction in the pathogenesis of Alzheimer's disease (AD). However, systematic comparative studies on the precise brain vasculature of wild-type and AD model mice are still rare. Using an image-optimization method for analysing Micro-Optical Sectioning Tomography (MOST) data, we generated cross-scale whole-brain 3D atlases that cover the entire vascular system from large vessels down to smallest capillaries at submicron resolution, for both wild-type mice and a transgenic (APP/PS1) mouse model of AD. In addition to distinct vascular patterns in different brain regions, we found that the main vessels of the molecular layer of the hippocampal dentate gyrus (DG-ml) undergo abrupt changes in both diameter and branch angle, spreading a unique comb-like pattern of capillaries. By using a quantitative analysis workflow, we identified in the hippocampus of AD mice an overall reduction of the mean vascular diameter, volume fraction and branch angle, with most significant impairment in the DG-ml. In addition, virtual endoscopy revealed irregular morphological features in the vessel lumen of the AD mice, potentially contributing to the impairment of blood flow. Our results demonstrate the capability of high-resolution cross-scale evaluation of brain vasculature and underscore the importance of studying hippocampal microcirculation for understanding AD pathogenesis.

Age-related changes in hippocampal AD pathology, actin remodeling proteins and spatial memory behavior of male APP/PS1 mice

Alzheimer's disease (AD) is the most common form of dementia in the elderly, characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Synaptic plasticity impairment is one of the early pathological events in AD. Transgenic APP/PS1 mice that overproduce Aβ are one of the most extensively used AD animal models. Many studies have investigated the roles of NTF-related p-Tau, non-amyloidogenic ADAM10, amyloidogenic BACE1, Aβ proteolytic NEP and IDE in certain ages of APP/PS1 mice as well as dendritic spine-related Rictor and Profilin-1 in normal mice, but there are few studies exploring the age-related changes of these molecules in the hippocampus of APP/PS1 mice. Furthermore, current studies regarding when memory impairment occurs in these mice are controversial. Thus, we examined the changes of these molecules in APP/PS1 and control mice using Western blot in mice 2–month-old (2 m) to 10 m of age and behavior changes using the Morris water maze from 4 m to 8 m. The results showed that in APP/PS1 mice, significant changes of hippocampal p-Tau, Aβ, ADAM10, BACE1 and Rictor occurred at 6 m, NEP at 8 m, and IDE and Profilin-1 at 10 m. In control mice, changes of p-Tau, ADAM10, and BACE1 occurred at 8 m and NEP at 10 m, while IDE, Rictor and Profilin-1 remained unchanged. Importantly, the Morris water maze test revealed that spatial memory impairment was detected at 8 m but not 4 or 6 m. The above findings clearly evidence that neurochemical changes overtly precede cognitive dysfunctions in this AD model and provide novel knowledge for a better understanding of the molecular events driving AD.

Visualizing Alzheimer\u2019s Disease Mouse Brain with Multispectral Optoacoustic Tomography using a Fluorescent probe, CDnir7

Alzheimer’s disease (AD) is now clinically considered as a chronic inflammation-based neurodegenerative disease. The CDnir7 probe was previously developed as an optical imaging probe to target macrophages in order to image mouse inflammation using in vivo optical imaging modalities such as In Vivo imaging system (IVIS) and fluorescent molecular tomography (FMT). Here, we demonstrate the application of CDnir7 in AD mouse brain imaging via multispectral optoacoustic tomography (MSOT). Longitudinal MSOT imaging of CDnir7 showed higher CDnir7 localization in AD mouse cerebral cortex compared to that of normal mice. MSOT signals of CDnir7 localization in mouse brain were verified by ex vivo near-infrared (NIR) imaging and immunohistochemistry. Histological evaluation showed strong CDnir7 staining in AD cerebral cortex, hippocampus, basal ganglia and thalamus area. Based on the supporting evidence, CDnir7 has great potential as a molecular imaging probe for AD brain imaging.

Pro-Nerve Growth Factor Induces Activation of RhoA Kinase and Neuronal Cell Death.

We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75NTR receptors. ProNGF is the precursor form of NGF, binds to p75NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75NTR expression and activation of RhoA, leading to neuronal cell death.

DNA methylation signature of human hippocampus in Alzheimer\u2019s disease is linked to neurogenesis

BackgroundDrawing the epigenome landscape of Alzheimer’s disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays.ResultsUp to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs.ConclusionsThese results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.Graphical abstract

Vinpocetine mitigates aluminum-induced cognitive impairment in socially isolated rats

Several reports have highlighted the role of vinpocetine in Alzheimer's disease (AD). However, the role of vinpocetine in AD under social isolation conditions has not yet been elucidated. Henceforth, this study aimed to investigate the potential neuroprotective effect of vinpocetine in aluminum-induced AD model associated with social isolation. Social isolation increased the escape latency in Morris water maze (MWM) test, elevated the immobility score and decreased swimming score in forced swimming test (FST) in aluminum treated rats. However, vinpocetine enhanced acquisition in MWM test and exerted anti-depressive effect in FST. The histopathological examination showed marked deterioration in the cerebral cortex and hippocampus of AD isolated rats, while vinpocetine revealed overt improvement. In addition, the levels of amyloid-β protein (Aβ), phosphorylated-tau (Ser396), malondialdehyde (MDA), interleukin 1-beta (IL-1β), tumor necrosis alpha (TNFα), p- Glycogen synthase kinase-3β (p-GSK3β) (Tyr216), and β-secretase (BACE1) gene expression were increased in socially isolated aluminum treated rats, yet, vinpocetine treatment reversed these deteriorating effects. Hence, this study provides profound insights into the role of vinpocetine in AD particularly in the conditions of social isolation. The effects of vinpocetine might be attributed not only to its antioxidant and anti-inflammatory properties, but also to its suppressing effect on GSK3β activity and its downstream BACE1.

Examination of Alzheimer's disease by a combination of electrostatic force and mechanical measurement.

Alzheimer's disease (AD) is the most common dementia and neurodegenerative disorder disease in central nervous system, and threatens the people's health seriously. But till now there are no effective ways to diagnose and treat AD. Herein, the differences between charge propagation, surface morphology, and Young's modulus of the hippocampus, in healthy and AD mice have been investigated using advanced modes of Atomic Force Microscopy (AFM). The ability of charge transfer in AD samples has decreased compared with healthy samples. There are compact layered structures in hippocampus from healthy sample, whereas there are no obvious layered structures in hippocampus from AD sample. The Young's modulus of hippocampus from AD sample is about half of that from healthy sample. The results demonstrate that AFM will be helpful in the further study of the functions of hippocampus and pathogenyof AD. LAY DESCRIPTION: Alzheimer's disease is the most common cause of dementia, a neurodegenerative disease which especially affects elderly people, threatens people's health seriously. The pathological features of AD are senile plaques, neurofibrillary tangles, and cerebral atrophy. The main clinical symptoms of AD are progressive memory impairment, cognitive dysfunction, and loss of language skills, as there are disorder in limbic and cortices. The morbidity rate increases with age and is currently at 5% and 20% among people older than 65 and 85, respectively. Thus AD has a heavy socioeconomic burden, especially in an aging society. So far, there are no effective therapeutic clinical treatments, and no effective means and methods to test and diagnose early stage AD. This means that further studies are essential to gain a deeper, fundamental understanding of the pathogenesis of AD. In this work, the surface morphology, electrical and mechanical properties of the hippocampi from healthy and AD mice have been investigated by Atomic Force Microscopy (AFM) at nanometre scale for the first time. The hippocampi from healthy mice are composed of compact layered structures, whereas there are no obvious characteristic features in the hippocampi from AD mice. The electrical properties of hippocampus slices were studied by the Electrostatic Force Microscopy (EFM) mode of AFM. The charge propagation ability of axons from AD mice has decreased dramatically compared to that of healthy mice. After charge injection (injection voltage was +10 V) the charge density was 2.3 × 105 Cμm-2 in healthy samples, which was larger than that from the AD samples (1.0 × 105 Cμm-2 ). The Young's modulus of hippocampi from healthy and AD mice were 104.0 and 40.1 kPa, respectively, as revealed by the quantitative nanomechanical mapping (QNM) mode of AFM. It indicates that when AD occurs, the Young's modulus will be lower than the healthy sample. These observations and experimental approaches will be useful in future studies of the pathogeny of AD.

Automated segmentation of medial temporal lobe subregions on in vivo T1-weighted MRI in early stages of Alzheimer's disease.

Medial temporal lobe (MTL) substructures are the earliest regions affected by neurofibrillary tangle pathology-and thus are promising biomarkers for Alzheimer's disease (AD). However, automatic segmentation of the MTL using only T1-weighted (T1w) magnetic resonance imaging (MRI) is challenging due to the large anatomical variability of the MTL cortex and the confound of the dura mater, which is commonly segmented as gray matter by state-of-the-art algorithms because they have similar intensity in T1w MRI. To address these challenges, we developed a novel atlas set, consisting of 15 cognitively normal older adults and 14 patients with mild cognitive impairment with a label explicitly assigned to the dura, that can be used by the multiatlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS-T1]) for the segmentation of MTL subregions, including anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex on T1w MRI. Cross-validation experiments indicated good segmentation accuracy of ASHS-T1 and that the dura can be reliably separated from the cortex (6.5% mislabeled as gray matter). Conversely, FreeSurfer segmented majority of the dura mater (62.4%) as gray matter and the degree of dura mislabeling decreased with increasing disease severity. To evaluate its clinical utility, we applied the pipeline to T1w images of 663 ADNI subjects and significant volume/thickness loss is observed in BA35, ERC, and posterior hippocampus in early prodromal AD and all subregions at later stages. As such, the publicly available new atlas and ASHS-T1 could have important utility in the early diagnosis and monitoring of AD and enhancing brain-behavior studies of these regions.

A novel strategy for rapidly and accurately screening biomarkers based on ultraperformance liquid chromatography-mass spectrometry metabolomics data

We reported a novel strategy for rapidly and accurately screening biomarkers based on ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) metabolomics data. First, the preliminary variables were obtained by screening the original variables using method validation. Second, the variables were selected from the preliminary variables and formed the variable sets by testing different thresholds of single factor (variable importance in projection (VIP), fold change (FC), the area under the receiver operating characteristic curve (AUROC), and –ln(p-value)). Then the partial least squares-discriminant analysis (PLS-DA) models were performed. The best threshold of each factor, and the corresponding variable set were found by comparing the models' R2X, R2Y, and Q2. Third, the second-step-obtained variable sets were further screened by multi-factors. The best combination of the multi-factors, and the corresponding variable set were found by comparing R2X, R2Y, and Q2. The expected biomarkers were thus obtained. The proposed strategy was successfully applied to screen biomarkers in urine, plasma, hippocampus, and cortex samples of Alzheimer's disease (AD) model, and significantly decreased the time of screening and identifying biomarkers, improved the R2X, R2Y, and Q2, therefore enhanced the interpreting, grouping, and predicting abilities of the PLS-DA model compared with generally-applied procedure. This work can provide a valuable clue to scientists who search for potential biomarkers. It is expected that the developed strategy can be written as a program and applied to screen biomarkers rapidly, efficiently and accurately.

Voluntary, involuntary and forced exercises almost equally reverse behavioral impairment by regulating hippocampal neurotrophic factors and oxidative stress in experimental Alzheimer's disease model.

The purpose of this study was to compare the neuroprotective effects of voluntary, involuntary, and forced exercise trainings on behavioral impairment as well as hippocampal Alzheimer's disease (AD) pathology and oxidative stress markers, and levels of neurotrophic factors in the rat model of AD. The rats were assigned to control, Alzheimer model, Alzheimer + voluntary exercise, Alzheimer + involuntary exercise, or Alzheimer + forced exercise group. The rat model of AD was established by D-(+)-Galactose (D-GAL) and AlCl3 administration for 90 days. Voluntary, involuntary (swimming) or forced exercise (load-swimming) trainings were performed for 90 days starting with the D-GAL and AlCl3 administration and then several behavioral tests were applied. Locomotor activity, exploratory behavior, and spatial memory were lower but anxiety levels were higher in the Alzheimer model group, than in the other groups (P < 0.05). The hippocampal levels of the amyloid beta 1-42, microtubule associated protein Tau, malondialdehyde, and protein carbonyl levels were higher, but brain-derived neurotrophic factor, nerve growth factor, glutathione and superoxide dismutase levels were lower in the Alzheimer model group, than in the other groups (P < 0.05). The results of the present study suggest that all exercise modalities almost equally attenuated non-cognitive and cognitive disturbances in a rat model of AD. Elevated neurotrophic factors, and improved oxidative stress could mediate these beneficial effects.

Glycosaminoglycans from Alzheimer's disease hippocampus have altered capacities to bind and regulate growth factors activities and to bind tau.

Glycosaminoglycans (GAGs), including heparan sulfates and chondroitin sulfates, are major components of the extracellular matrix. Upon interacting with heparin binding growth factors (HBGF), GAGs participate to the maintaintenance of tissue homeostasis and contribute to self-healing. Although several processes regulated by HBGF are altered in Alzheimer’s disease, it is unknown whether the brain GAG capacities to bind and regulate the function of HBGF or of other heparin binding proteins, as tau, are modified in this disease. Here, we show that total sulfated GAGs from hippocampus of Alzheimer’s disease have altered capacities to bind and potentiate the activities of growth factors including FGF-2, VEGF, and BDNF while their capacity to bind to tau is remarkable increased. Alterations of GAG structures and capacities to interact with and regulate the activity of heparin binding proteins might contribute to impaired tissue homeostasis in the Alzheimer’s disease brain.

Epigenetic mechanisms underlying the effects of triptolide and tripchlorolide on the expression of neuroligin-1 in the hippocampus of APP/PS1 transgenic mice

Context: Neuroligin-1 (NLGN1) is a cell adhesion protein located on the excitatory postsynaptic membrane. β-Amyloid (Aβ)-induced neuroinflammation decreases NLGN1 expression through epigenetic mechanisms. Triptolide (T10) and tripchlorolide (T4) exert protective effects on synapses in Alzheimer's disease (AD) mice, but the mechanisms remain unclear.Objective: The effects of T10 and T4 on hippocampal NLGN1 expression in AD mice and the epigenetic mechanisms were assessed using chromatin immunoprecipitation and methylated DNA immunoprecipitation.Materials and methods: Sixty APP/PS1 transgenic mice were randomly divided into an AD model group, a T10-treated group and a T4-treated group (n = 20); 20 wild-type littermates served as the control group. APP/PS1 transgenic mice were intraperitoneally injected with T10 (0.1 mg/kg) and T4 (25 μg/kg) once per day for 60 days. NLGN1 expression was examined using western blotting and quantitative PCR.Results: T10 and T4 increased the levels of the NLGN1 protein and mRNA in hippocampus of AD mice. T10 and T4 inhibited the binding of HDAC2 (p< 0.01) and MeCP2 (p< 0.01 and p< 0.05, respectively) to the NLGN1 promoter, and cytosine methylation (1.2305 ± 0.1482/1.2554 ± 0.3570 vs. 1.6578 ± 0.1818, p< 0.01) at the NLGN1 promoter in the hippocampus of AD mice. T10 and T4 increased the level of acetylated histone H3 (0.7733 ± 0.1611/0.8241 ± 0.0964 vs. 0.5587 ± 0.0925, p< 0.01) at the NLGN1 promoter in the hippocampus of AD mice.Conclusions: T10 and T4 may increase hippocampal NLGN1 expression in AD mice through epigenetic mechanisms, providing a new explanation for the mechanism underlying the protective effects of T10 and T4 on synapses.

AmpliSeq Transcriptome of Laser Captured Neurons from Alzheimer Brain: Comparison of Single Cell Versus Neuron Pools.

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. However, the pathogenesis of AD remains to be fully understood and clinically effective treatments are lacking. Recent advances in single cell RNA sequencing offers an opportunity to characterize the heterogeneity of cell response and explore the molecular mechanism of complex diseases at a single cell level. Here, we present the application of the Ion AmpliSeq transcriptome approach to profile gene expression in single laser captured neurons as well as pooled 10 and 100 neurons from hippocampal CA1 of AD brains versus matching normal aged brains. Our results demonstrated the high sensitivity and high genome coverage of the AmpliSeq transcriptome in single cell sequencing. In addition to capturing the known changes related to AD, our data confirmed the diversity of neuronal profiles in AD brain, which allow the potential identification of single cell response that might be hidden in population analyses. Notably, we also revealed the extensive inhibition of olfactory signaling and confirmed the reduction of neurotransmitter receptors in AD hippocampus. We conclude that although single neuron data show more variance than data from 10 or 100 pooled neurons, single neuron data can be informative. These findings support the utility of the Ion AmpliSeq method for obtaining and analyzing gene expression data from single defined laser captured neurons.

The Effects of Six Weeks High Intensity Interval Training on Amyloid Beta1-42 Peptide in Hippocampus of Rat Model of Alzheimer's Disease Induced with STZ

Background: Alzheimer's disease is the formaton of amyloid beta (Aβ) plaques and tau tangles in the brain. As Aβ is an important factor in the pathogenesis of Alzheimer's disease, the present research aims to consider the effects of six weeks of high intensity interval training on Aβ1-42 levels in the hippocampus tissue of male rat models of Alzheimer’s disease. Methods: Thirty-five rats (3 months old, 222.83 ± 19.60 g) were divided into five groups: Two experimental, two control and sham. Alzheimer's disease, induced by streptozotocin was infused into the rats i.c.v (a 3 m.g/kg dose). Their memory was evaluated by passive avoidance learning method using a shuttle box. The amount of peptide Aβ1-42 was measured by the ELISA method. Comprisions between groups were performed by One-way ANOVA followed by Tukey test. A value of P < 0.05 was considered to be significant. Results: The Aβ1-42 levels in the hippocampus of Alzheimer's control group was significantly higher than Alzheimer's HIIT group (P = 0.036) and it was lower in the health HIIT group than it was in the health control group (P = 0.001). Conclusions: It declare that HIIT training lessen the level of Aβ1-42 in the hippocampus and can be benefit for AD rat model. As a result, the advantages of HIIT training can be used in protection and treatment of AD.

Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology.

Microglial cells are crucial players in the pathological process of neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglial response in AD has been principally studied in relation to amyloid-beta pathology but, comparatively, little is known about inflammatory processes associated to tau pathology. In the hippocampus of AD patients, where tau pathology is more prominent than amyloid-beta pathology, a microglial degenerative process has been reported. In this work, we have directly compared the microglial response in two different transgenic tau mouse models: ThyTau22 and P301S. Surprisingly, these two models showed important differences in the microglial profile and tau pathology. Where ThyTau22 hippocampus manifested mild microglial activation, P301S mice exhibited a strong microglial response in parallel with high phospho-tau accumulation. This differential phospho-tau expression could account for the different microglial response in these two tau strains. However, soluble (S1) fractions from ThyTau22 hippocampus presented relatively high content of soluble phospho-tau (AT8-positive) and were highly toxic for microglial cells in vitro, whereas the correspondent S1 fractions from P301S mice displayed low soluble phospho-tau levels and were not toxic for microglial cells. Therefore, not only the expression levels but the aggregation of phospho-tau should differ between both models. In fact, most of tau forms in the P301S mice were aggregated and, in consequence, forming insoluble tau species. We conclude that different factors as tau mutations, accumulation, phosphorylation, and/or aggregation could account for the distinct microglial responses observed in these two tau models. For this reason, deciphering the molecular nature of toxic tau species for microglial cells might be a promising therapeutic approach in order to restore the deficient immunological protection observed in AD hippocampus.

Default Mode Network Complexity and Cognitive Decline in Mild Alzheimer's Disease.

The human resting-state is characterized by spatially coherent brain activity at a low temporal frequency. The default mode network (DMN), one of so-called resting-state networks, has been associated with cognitive processes that are directed toward the self, such as introspection and autobiographic memory. The DMN’s integrity appears to be crucial for mental health. For example, patients with Alzheimer’s disease or other psychiatric conditions show disruptions of functional connectivity within the brain regions of the DMN. However, in prodromal or early stages of Alzheimer’s disease, physiological alterations are sometimes elusive, despite manifested cognitive impairment. While functional connectivity assesses the signal correlation between brain areas, multi-scale entropy (MSE) measures the complexity of the blood-oxygen level dependent signal within an area and thus might show local changes before connectivity is affected. Hence, we investigated alterations of functional connectivity and MSE within the DMN in fifteen mild Alzheimer’s disease patients as compared to fourteen controls. Potential associations of MSE with functional connectivity and cognitive abilities [i.e., mini-mental state examination (MMSE)] were assessed. A moderate decrease of DMN functional connectivity between posterior cingulate cortex and right hippocampus in Alzheimer’s disease was found, whereas no differences were evident for whole-network functional connectivity. In contrast, the Alzheimer’s disease group yielded lower global DMN-MSE than the control group. The most pronounced regional effects were localized in left and right hippocampi, and this was true for most scales. Moreover, MSE significantly correlated with functional connectivity, and DMN-MSE correlated positively with the MMSE in Alzheimer’s disease. Most interestingly, the right hippocampal MSE was positively associated with semantic memory performance. Thus, our results suggested that cognitive decline in Alzheimer’s disease is reflected by decreased signal complexity in DMN nodes, which might further lead to disrupted DMN functional connectivity. Additionally, altered entropy in Alzheimer’s disease found in the majority of the scales indicated a disturbance of both local information processing and information transfer between distal areas. Conclusively, a loss of nodal signal complexity potentially impairs synchronization across nodes and thus preempts functional connectivity changes. MSE presents a putative functional marker for cognitive decline that might be more sensitive than functional connectivity alone.