Subcutaneous transplantation of mesenchymal stem cell spheroids ameliorates cognitive deficits in Alzheimer's disease.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

The overlap between Alzheimer's disease and epilepsy uncovered by transcriptome sequencing

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

The investigation of Alzheimer disease (AD) with neuroimaging has often focused on 2 different brain regions. Researchers using positron emission tomographic (PET) imaging of glucose metabolism with fludeoxyglucose F 18 described hypometabolism in the lateral temporoparietal cortex and especially the medial parietal cortex encompassing the precuneus and posterior cingulate.1 Investigations using magnetic resonance imaging showed that patients with AD had substantial atrophy in the medial temporal lobes (MTLs), specifically the hippocampus and entorhinal cortex. Considerable work has extended these findings to individuals who may be in early stages of AD as reflected by mild cognitive impairment. Although subsequently it has become clear that involvement of these anatomical areas is not modality specific (that is, medial temporal hypometabolism and medial parietal atrophy are both reported in AD), the pathological relationship of degeneration in these 2 brain regions has been difficult to understand. Imagingbiomarkershave linked these regional changes to pathology, but this has raised more questions. Amyloid PET imaginghasmade it clear that theprecuneusandposterior cingulate are the site of relatively early deposition of β-amyloid (Aβ), thecentralprotein in the AD plaque. About a third of cognitively normal older people have brainAβdeposition, andwhen present, it almost invariably occurs in this region. However, the MTL, at least in early stages, is relatively devoid of Aβ, as seen at postmortem examination and with amyloid PET imaging. Postmortem studies, however, have linked theMTL strongly to the other key pathology of AD, the neurofibrillary tangle,2 reflectingpathological formsof the tau protein. This further establishes a major mystery of AD: how areamyloidpathology in themedial parietal cortexand taupathology in the MTL related? These 2 structures are linked through their participation inaneural systemknownas thedefaultmodenetwork (DMN). Thisnetworkhasbeenstudied invivousing resting-state functional connectivitymagnetic resonance imaging. By examiningthespontaneoussynchronyof thefunctionalmagnetic resonance imaging signal, functional network connections are detectedat rest thatparallel brainnetworks that areactiveduring specific types of cognitive tasks. The DMN is a tasknegative network that is deactivatedduring externally driven cognition but becomes active during introspective processes such as future planning and memory recall. It is also of particular interest because it becomes disconnected in patients withADand in cognitively normal older peoplewhohave evidence of brain Aβ on amyloid PET imaging. Thus, probing the functional connectivity of the DMN can provide insight into relationships between2major nodesof this network, theMTL andmedial parietal cortex. Wang et al3 examined changes in the DMN in 207 cognitively normal older people who had cerebrospinal fluid obtained for themeasurement of Aβ42 andphosphorylated tau. Lower levels of CSFAβ42 arewidely reported to parallel brain deposition of Aβ seenwith PET. Thus, it is not surprising that lower CSF Aβ42 in this study was associated with disconnection of the DMN since previous PET studies revealed similar findings. Within this network, however, Aβ42 affected connectivitybetween theposterior cingulate cortex (PCC) and the MTLmore thanconnectionsbetween thePCCandothernodes of the network. Biomarkers of tau are largely thought to indicate a stage later in the pathological progression of AD than Aβbecause theyare regardedas indicativeofAβ-initiatedneurodegeneration. In this study,phosphorylated taualso showed a relationshipwith connectivity such that higher levels of CSF phosphorylated tau were associated with PCC and MTL disconnection. In thesedata, the findings foreachbiomarkerwere present while controlling for the other, and the effects were not explained by age or atrophy of the relevant brain regions. Thiswork thusextendspreviousdataby showingnetworkdisconnection in asymptomatic individuals in a particularly important pathway and showing that this effect is seen for biomarkers reflecting both amyloid and neurodegenerative processes. It also provides hints about how these 2 pathological processes and anatomical regions might be related. Fromaclinical perspective, the results suggest that a relatively simple magnetic resonance imaging measure might be a reasonablebiomarker for earlyAD.Thecaveats, however, are substantial. Forexample, technical factors inassessing restingstate networks are crucial: small amounts of headmotion can produce artifacts that are difficult to detect, there are multiple approaches todata analysis, and reliability over timeand across centers has not been extensively established. Furthermore, validating this approach as a biomarker requires much stronger links todiseasephenotypes that include theprogression to AD dementia. Nevertheless, the appeal of this technique is that it can be performed on available clinical instruments, requires no particular cognitive task, and can be obtained in a fewminutes. Targeting 2brain regions for analysis—the PCC and the MTL—could be a simple and widely applicabledata-analytic approach to trackearlydisease if thedifficult technical issues, predictive value, sensitivity, and specificity can be worked out. Regardless of the clinical utility, the data presented by Wang et al3 show that changes in 2 different biomarkers reflectingdifferent aspects ofADpathological progressionaffect Related article page 1242 Opinion

Decision letter: Model-based whole-brain perturbational landscape of neurodegenerative diseases

Editor's evaluation: Model-based whole-brain perturbational landscape of neurodegenerative diseases

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.

Saponin of Rhizoma Polygonati (SRP) is a key bioactive component obtained from Rhizoma Polygonati, has neuroprotection, antioxidant and anticancer effects. This research aimed to explore whether SRP improves cognitive deficits in Alzheimer's disease (AD) mice. Behavioral testing was performed by the Morris water maze test. Histopathological changes and neuronal apoptosis in mouse hippocampus were observed by Hematoxylin-eosin, Nissl staining, and TUNEL staining. The impact of SRP on amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) production was determined by immunofluorescence and Glycine silver staining. Western blot detected c-Abl/Mammalian sterile 20 (STE20)-like kinase 1 (MST1) pathway, apoptosis-related protein, and Tau phosphorylation level. AD mice exhibit cognitive deficits compared to normal mice, and SRP ameliorates cognitive deficits. The hippocampal tissues of AD mice showed neuronal damage and apoptosis, with Aβ deposition, loss of Nissl bodies and formation of NFTs. SRP attenuated neuronal damage in AD mice, inhibited Aβ deposition and NFTs formation. Additionally, SRP blocked the c-Abl/MST1 pathway in AD mice. c-Abl inhibitor enhanced the neuroprotective effect of SRP in AD mice, while c-Abl agonist weakened this effect. SRP inhibits hippocampal histopathological damage and enhances cognitive ability in AD mice through blocking the c-Abl/MST1 pathway.

Salidroside administration improves memory in different models of learning. However, its influence on models of Alzheimer's disease (AD) has not been widely studied. In the present study, the therapeutic effect of salidroside was investigated in an animal model of AD. APPswe/PS1ΔE9 mouse (n=20) were randomly divided into either the AD model group or the salidroside+AD model group (n=10 in each group), and C57BL/6J mouse (n=20) of identical age and genetic background were randomly divided into either the normal control (NC) group or the salidroside+NC group (n=10 in each group). The Morris water maze behavioral test was applied to all mice in order to investigate the effects of salidroside administration on learning and memory functions. The concentrations of malondialdehyde (MDA), glutathione(GSH) and nitrate in the hippocampus of the mice were determined, and hippocampal superoxide dismutase (SOD) activity was also determined. In addition, terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling was used to investigate the rate of neuronal apoptosis in the hippocampus. Furthermore, the concentrations of interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) were tested for in the brain tissues of AD mice. Learning and memory functions in AD mice were revealed to improve following administration of salidroside. Furthermore, salidroside administration was revealed to decrease the concentrations of MDA and nitrate in the hippocampus, decrease the apoptotic rate of hippocampal neurons, and increase the activity of SOD and the concentration of GSH in hippocampal tissue. In addition, it was demonstrated that salidroside administration suppressed the expression levels of IL‑6 and TNF‑α. In conclusion, this study revealed that the administration of salidroside could attenuate the effects of AD‑associated memory and learning impairment in mice. Furthermore, it was demonstrated that the effects of salidroside administration on AD mice were, at least partially, via inhibition of brain oxidative/nitrosative damage, suppression of both IL‑6 and TNF‑α expression levels, and suppression of the hippocampal neuronal apoptotic rate.

Abnormal insula functional network is associated with episodic memory decline in amnestic mild cognitive impairment

Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.

Atrophy of the subiculum is the earliest hippocampal anatomical marker of Alzheimer’s disease (AD) and is closely associated with early cognitive decline. However, the underlying mechanisms driving this vulnerability remain unclear. In this study, using the 5×FAD mouse model, we identified significant amyloid-beta (Aβ) accumulation in the subiculum during the early stages of AD. Through a combination of laser microdissection and proteomic analysis, we uncovered early dysregulation of GABAergic neurons in the subiculum. Further investigation revealed that parvalbumin (PV) interneurons (PV-INs) were key drivers of Aβ pathology, exhibiting pronounced hyperactivity during the initial stages of AD. Targeted inhibition of this PV interneuron hyperactivity at the onset of AD, using chemogenetic approaches and PV downregulation, significantly reduced Aβ accumulation in the subiculum and connected brain regions, while also enhancing cognitive function in AD mice. Supporting these findings, single-nucleus RNA sequencing (snRNA-seq) data from human AD patients revealed that PV expression in GABAergic neurons peaks at early stages of the disease, further reinforcing the role of PV interneuron hyperactivity in early AD progression. Additionally, PV interneuron inhibition restored protein homeostasis by normalizing GABAergic synapses, improving lysosomal function, and promoting APP degradation via K63-linked ubiquitination. These results provide critical insights into the cellular mechanisms that drive early Aβ pathology in the subiculum, positioning subicular PV-INs as promising therapeutic targets for early intervention in AD.

ObjectiveTo investigate the role of toll like receptor 4 (TLR4) in the cognition impairment in β‐amyloid fragment 1–42 (Aβ1–42) induced Alzheimer's disease (AD) mouse model.MethodsTwenty four TLR4 gene knockout mice (TLR4KO, male, body weight: 25–30g) and 24 wild type mice (WT, male, body weight: 25–30g) were randomly assigned into 4 groups: Normal saline control (WT.NS, wild type mice were injected 1ul normal saline into bilateral hippocampus), AD model group (WT. Aβ, wild type mice were injected with 1ul Aβ1–42 (5ug/ul) into bilateral hippocampus), TLR4KO‐normal saline control (TLR4KO.NS, TLR4KO mice were injected with 1ul normal saline into bilateral hippocampus), and TLR4KO Aβ group (TLR4KO.Aβ, TLR4KO mice were injected with 1ul Aβ1–42 (5ug/ul) into bilateral hippocampus). Seven days after injection, the learning and memorial functions were tested using Morris Water Maze (MWM). The repeated measures analysis of variance was used to analyze navigation test, the one‐way ANOVA and LSD post‐hoc comparisons were used for probe trial analyses. HE staining was performed.; and the expression of Bcl‐2 and Caspase‐3 was assayed by Western blot, the results was analyzed by one‐way ANOVA.Results1. Compared with normal saline control groups(WT.NS), the AD groups (WT. Aβ) showed a longer escape latency (P&lt;0.05), increased percentage of time in outer annulus (P&lt;0.05) in the place navigation test, reduced percentage of time in the platform quadrant and decreasing times of traversing platform (P&lt;0.05) in the spatial probe test. Compared with AD model groups(WT.Aβ), the escape latency and the percentage of time in outer annulus were decreased in TLR4KOAβ groups (P&lt;0.05), and the percentage of time in the platform quadrant and the times of traversing platform were increased (P&lt;0.05). There was no significant difference of swimming speed amonge each group (P&gt;0.05). 2. Hematoxylin eosin staining showed that compared with normal saline control groups, the neurons in AD groups distribute loosely and irregularly, and more dead neurons were observed. TLR4KOAβ groups showed a attenuated damage in hippocamus compared with the AD groups. 3. The results of western blots suggested that compared with control groups, the expression of Bcl‐2 in AD groups were significant reduced (P&lt;0.05) and the expression of Caspase‐3 were increased (P&lt;0.05); the expression of Bcl‐2 in the TLR4KO Aβ groups were increased (P&lt;0.05) and the level of Caspase‐3 was reduced (P&lt;0.05) when compared with AD groups.Conclusion1. Injection of 5ug Aβ1–42 into bilateral hippocampus can obvious impaire the learning and memorial functions and induced histological damage in hippocampus of mice, which provides an effective method for establishing mouse model of AD; 2. TLR4 knockout can attenuate cognitive impairment and tissue damage induced by hippocampal injection of Aβ1–42 in the AD model, which may be partly achieved by reducing apoptosis.Support or Funding InformationThis work was supported by China National Nature Scientific Foundation (81571469 and 81271268)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evaluation of suprachiasmatic nucleus in Alzheimer’s disease with non-invasive magnetic resonance methods

Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APPswe/PS1dE9 mice