Memory Deficits In Alzheimer's Disease Research Articles

Study on the role of Dihuang Yinzi in regulating the AMPK/SIRT1/PGC-1α pathway to promote mitochondrial biogenesis and improve Alzheimer's disease

Ethnopharmacological relevanceDihuang Yinzi (DHYZ) is a classic prescription in traditional Chinese medicine. Its therapeutic effect on Alzheimer's disease (AD) has been widely validated. However, the underlying molecular mechanisms of DHYZ in AD treatment remain unclear and require further research. Aim of the studyElucidating DHYZ's promotion of mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α pathway improves neuronal loss, mitochondrial damage, and memory deficits in AD. Materials and methodsAdministering DHYZ by gavage to SAMP8 mice, after completing behavioral tests, the effects of DHYZ on hippocampal neuron loss and mitochondrial structural damage in AD model mice were assessed using Nissl staining and transmission electron microscopy. Western blot was used to detect the expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, mitochondrial fusion protein MFN2, and mitochondrial fission proteins DRP1 and FIS1. At the same time, immunofluorescence (IF) was employed to measure the relative fluorescence intensity of mitochondrial fusion protein MFN1. After determining the optimal dose of DYHZ for treating AD, we conducted mechanistic studies. By intraperitoneally injecting SAMP8 mice with the AMPK inhibitor (Compound C) to inhibit AMPK protein expression and subsequently treating them with DHYZ, the impact of DHYZ on hippocampal neurons in AD model mice was evaluated using Nissl and hematoxylin-eosin staining. Western blot was used to detect the protein expression of AMPK, p-AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In contrast, IF was used to measure the relative fluorescence intensity of PGC-1α, NRF1, and TFAM proteins in the hippocampal CA1 region. ResultsDHYZ significantly improved AD model mice's cognitive impairment and memory deficits and mitigated hippocampal neuron loss and degeneration. Additionally, it ameliorated mitochondrial morphological structures. DHYZ upregulated the protein expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, and mitochondrial fusion proteins MFN1 and MFN2 while inhibiting the expression of mitochondrial fission proteins DRP1 and FIS1. Further studies revealed that DHYZ could upregulate the expression of the AMPK/SIRT1/PGC-1α pathway proteins and their downstream proteins NRF1 and TFAM. ConclusionDHYZ promotes mitochondrial biogenesis by activating the AMPK/SIRT1/PGC-1α signaling pathway, thereby improving memory deficits, neuronal loss, and mitochondrial dysfunction in AD.

Memory encoding and retrieval by retrosplenial parvalbumin interneurons are impaired in Alzheimer’s disease model mice

Memory deficits in Alzheimer's disease (AD) show a strong link with GABAergic interneuron dysfunctions.1,2,3,4,5,6,7 The ensemble dynamics of GABAergic interneurons represent memory encoding and retrieval,8,9,10,11,12 but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As the retrosplenial cortex (RSC) is critical for episodic memory13,14,15,16 and is affected by β-amyloid accumulation in early AD,17,18,19,20,21 we address this question by performing Ca2+ imaging in RSC parvalbumin (PV)-expressing interneurons during a contextual fear memory task in healthy control mice and the 5XFAD mouse model of AD. We found that populations of PV interneurons responsive to aversive electric foot shocks during contextual fear conditioning (shock-responsive) significantly decreased in the 5XFAD mice, indicating dysfunctions in the recruitment of memory-encoding PV interneurons. In the control mice, ensemble activities of shock-responsive PV interneurons were selectively upregulated during the freezing epoch of the contextual fear memory retrieval, manifested by synaptic potentiation of PV interneuron-mediated inhibition. However, such changes in ensemble dynamics during memory retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during contextual fear conditioning in the control mice mimicked the memory deficits in the 5XFAD mice, while optogenetic activation of PV interneurons in the 5XFAD mice restored memory retrieval. These results demonstrate the critical roles of contextual fear memory-encoding PV interneurons for memory retrieval. Furthermore, synaptic dysfunction of PV interneurons may disrupt the recruitment of PV interneurons and their ensemble dynamics underlying contextual fear memory retrieval, subsequently leading to memory deficits in AD.

Alterations via inter-regional connective relationships in Alzheimer's disease.

Disruptions in the inter-regional connective correlation within the brain are believed to contribute to memory impairment. To detect these corresponding correlation networks in Alzheimer's disease (AD), we conducted three types of inter-regional correlation analysis, including structural covariance, functional connectivity and group-level independent component analysis (group-ICA). The analyzed data were obtained from the Alzheimer's Disease Neuroimaging Initiative, comprising 52 cognitively normal (CN) participants without subjective memory concerns, 52 individuals with late mild cognitive impairment (LMCI) and 52 patients with AD. We firstly performed vertex-wise cortical thickness analysis to identify brain regions with cortical thinning in AD and LMCI patients using structural MRI data. These regions served as seeds to construct both structural covariance networks and functional connectivity networks for each subject. Additionally, group-ICA was performed on the functional data to identify intrinsic brain networks at the cohort level. Through a comparison of the structural covariance and functional connectivity networks with ICA networks, we identified several inter-regional correlation networks that consistently exhibited abnormal connectivity patterns among AD and LMCI patients. Our findings suggest that reduced inter-regional connectivity is predominantly observed within a subnetwork of the default mode network, which includes the posterior cingulate and precuneus regions, in both AD and LMCI patients. This disruption of connectivity between key nodes within the default mode network provides evidence supporting the hypothesis that impairments in brain networks may contribute to memory deficits in AD and LMCI.

A Neuroligin-1 mutation associated with Alzheimer’s disease produces memory and age-dependent impairments in hippocampal plasticity

Alzheimer's disease (AD) is characterized by memory impairments and age-dependent synapse loss. Experimental and clinical studies have shown decreased expression of the glutamatergic protein Neuroligin-1 (Nlgn1) in AD. However, the consequences of a sustained reduction of Nlgn1 are unknown. Here, we generated a knockin mouse that reproduces the NLGN1 Thr271fs mutation, identified in heterozygosis in a familial case of AD. We found that Nlgn1 Thr271fs mutation abolishes Nlgn1 expression in mouse brain. Importantly, heterozygous Nlgn1 Thr271fs mice showed delay-dependent amnesia for recognition memory. Electrophysiological recordings uncovered age-dependent impairments in basal synaptic transmission and long-term potentiation (LTP) in CA1 hippocampal neurons of heterozygous Nlgn1 Thr271fs mice. In contrast, homozygous Nlgn1 Thr271fs mice showed impaired fear-conditioning memory and normal basal synaptic transmission, suggesting unshared mechanisms for a partial or total loss of Nlgn1. These data suggest that decreased Nlgn1 may contribute to the synaptic and memory deficits in AD.

Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer's disease.

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.

TARGETING MENINGEAL LYMPHATICS AS A THERAPEUTIC STRATEGY FOR ALZHEIMER's DISEASE: A NOVEL APPLICATION OF CRANIAL BONE MANOEUVRE

Based on Ilizarov's law of tension-stress principle, distraction histogenesis technique has been widely applied in orthopaedic surgery for decades. Derived from this technique, cranial bone transport technique was mainly used for treating cranial deformities and calvarial defects. Recent studies reported that there are dense short vascular connections between skull marrow and meninges for immune cells trafficking, highlighting complex and tight association between skull and brain. Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia without effective therapy. Meningeal lymphatics have been recognized as an important mediator in neurological diseases. The augmentation of meningeal lymphatic drainage might be a promising therapeutic target for AD. Our proof-of-concept study has indicated that cranial bone transport can promote ischemic stroke recovery via modulating meningeal lymphatic drainage function, providing a rationale for treating AD using cranial bone maneuver (CBM). This study aims to investigate the effects of CBM on AD and to further explore the potential mechanisms.Transgenic 5xFAD mice model was used in this study. After osteotomy, a bone flap was used to perform CBM without damaging the dura. Open filed test, novel object recognition test and Barn's maze test were used to evaluate neurological functions of 5xFAD mice after CBM treatment. Congo red and immunofluorescence staining were used to evaluate amyloid depositions and Aβ plaques in different brain regions. Lymphangiogenesis and the level of VEGF-C were examined after CBM treatment. OVA-A647 was intra-cisterna-magna injected to evaluate meningeal lymphatic drainage function after CBM treatment.CBM significantly improved memory functions and reduced amyloid depositions and Aβ plaques in the hippocampus of 5xFAD mice. A significant increase of meningeal lymphatic vessels in superior sagittal sinus and transverse sinus, and the upregulation of VEGF-C in meninges were observed in 5xFAD mice treated with CBM. Moreover, CBM remarkably enhanced meningeal lymphatic drainage function in 5xFAD mice (n=5-16 mice/group for all studies).CBM may promote meningeal lymphangiogenesis and lymphatic drainage function through VEGF-C-VEGFR3 pathway, and further reduce amyloid depositions and Aβ plaques and alleviate memory deficits in AD.

Adult neurogenesis in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.

Attenuation of HECT-E3 ligase expression rescued memory deficits in 3xTg-AD mice

Alzheimer's disease (AD) is one of the most common progressive neurodegenerative disorders that cause deterioration of cognitive functions. Recent studies suggested that the accumulation of inflammatory molecules and impaired protein degradation mechanisms might both play a critical role in the progression of AD. Autophagy is a major protein degradation pathway that can be controlled by several HECT-E3 ligases, which then regulates the expression of inflammatory molecules. E3 ubiquitin ligases are known to be upregulated in several neurodegenerative diseases. Here, we studied the expressional change of HECT-E3 ligase using M01 on autophagy and inflammasome pathways in the context of AD pathogenesis. Our results demonstrated that the M01 treatment reversed the working memory deficits in 3xTg-AD mice when examined with the T-maze and reversal learning with the Morris water maze. Additionally, the electrophysiology recordings indicated that M01 treatment enhanced the long-term potentiation in the hippocampus of 3xTg-AD mice. Together with the improved memory performance, the expression levels of the NLRP3 inflammasome protein were decreased. On the other hand, autophagy-related molecules were increased in the hippocampus of 3xTg-AD mice. Furthermore, the protein docking analysis indicated that the binding affinity of M01 to the WWP1 and NEDD4 E3 ligases was the highest among the HECT family members. The western blot analysis also confirmed the decreased expression level of NEDD4 protein in the M01-treated 3xTg-AD mice. Overall, our results demonstrate that the modulation of HECT-E3 ligase expression level can be used as a strategy to treat early memory deficits in AD by decreasing NLRP3 inflammasome molecules and increasing the autophagy pathway.

Effects of cocoa on altered metabolite levels in purine metabolism pathways and urea cycle in Alzheimer's disease in C. elegans

Dietary interventions have gained much attention as alternative therapies in aging-associated diseases. Epidemiological studies suggest that polyphenols (PPs) play an important role in this regard. Cocoa is rich in PPs, greater in amount than in teas and red wine. This study aimed to characterize the age-associated and amyloid-β (Aβ)-induced changes in metabolism in C. elegans and the effects of cocoa supplementation. An untargeted Gas Chromatography-Mass Spectrometry (GC-MS) approach was used to determine the changes in endogenous metabolite levels in wild-type and a transgenic C. elegans strain expressing pan-neuronal Aβ (GRU102). Aging appeared to alter some amino acid levels in C. elegans. Cocoa supplementation reduced leucine and tyrosine levels in old age (day 12). GRU102 showed higher proline and asparagine relative to control worms at a young age (day 4) which may have a connection with cognitive deficits in Alzheimer's disease (AD). Cocoa reduced the elevated levels of these two amino acids to the levels in the control worms. The purine derivative, hypoxanthine was higher in GRU102 relative to the control worms at their middle age (day 8) where the elevated are known to contribute to memory deficits in AD. Cocoa supplementation reduced the elevated hypoxanthine to normal levels. Aβ expression showed alterations in the urea cycle in worms in their middle age as indicated by increased ornithine.

Deficient semantic knowledge of the life course-Examining the cultural life script in Alzheimer's disease.

Cultural life scripts are culturally transmitted semantic knowledge of the expected order and timing of major transitional events in a prototypical life course. This cognitive schema has been shown to serve as an important mnemonic template that guides retrieval from autobiographical memory, especially for positive and important life events. Autobiographical memory deficits are one of the earliest and most prominent symptoms in Alzheimer's disease (AD). However, no studies have examined cultural life scripts in patients with AD, despite semantic memory impairments being reported even in the early stages of the disease. The aim of the present work was to assess life-script knowledge in older adults diagnosed with AD, particularly in terms of knowledge for the content of life-script events and the timing and temporal order of these events. Twenty-one older adults diagnosed with AD and 22 healthy age-matched controls completed the standard life-script task (Berntsen & Rubin, 2004, Memory & Cognition, 32[3], 427-442). We found that while AD patients produced significantly fewer life-script events, the content of the generated events were quite consistent with those of the controls and the cultural norms. AD patients were particular impaired with regard to the normative timing and order of life-script events, suggesting that these components of the cultural life script are more vulnerable to cognitive decline. The findings are discussed in relation to impaired script knowledge and semantic memory deficits in AD.

Hippocampal sub-networks exhibit distinct spatial representation deficits in Alzheimer’s disease model mice

Not much is known about how the dentate gyrus (DG) and hippocampal CA3 networks, critical for memory and spatial processing, malfunction in Alzheimer's disease (AD). While studies of associative memory deficits in AD have focused mainly on behavior, here, we directly measured neurophysiological network dysfunction. We asked what the pattern of deterioration of different networks is during disease progression. We investigated how the associative memory-processing capabilities in different hippocampal subfields are affected by familial AD (fAD) mutations leading to amyloid-β dyshomeostasis. Specifically, we focused on the DG and CA3, which are known to be involved in pattern completion and separation and are susceptible to pathological alterations in AD. To identify AD-related deficits in neural-ensemble dynamics, we recorded single-unit activity in wild-type (WT) and fAD model mice (APPSwe+PSEN1/ΔE9) in a novel tactile morph task, which utilizes the extremely developed somatosensory modality of mice. As expected from the sub-network regional specialization, we found that tactile changes induced lower rate map correlations in the DG than in CA3 of WT mice. This reflects DG pattern separation and CA3 pattern completion. In contrast, in fAD model mice, we observed pattern separation deficits in the DG and pattern completion deficits in CA3. This demonstration of region-dependent impairments in fAD model mice contributes to understanding of brain networks deterioration during fAD progression. Furthermore, it implies that the deterioration cannot be studied generally throughout the hippocampus but must be researched at a finer resolution of microcircuits. This opens novel systems-level approaches for analyzing AD-related neural network deficits.

CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating β‑amyloid metabolism‑associated enzymes.

Alzheimer's disease (AD) is the most common form of dementia that is primarily characterized by progressive cognitive deficits. The toxicity of amyloid β-protein (Aβ) serves an important role in the progression of AD, resulting in neuronal loss via a number of possible mechanisms, including oxidative stress, mitochondrial dysfunction, energy depletion, apoptosis and neuroinflammation. Previous studies have reported that cocaine amphetamine regulated transcript (CART) treatment improves memory and synaptic structure in APP/PS1 mice. Therefore, the present study aimed to investigate whether CART served a protective role against memory deficits in AD. APP/PS1 mice were treated with CART or PBS. Spatial memory was assessed using the Morris water maze. Oxidative stress and DNA damage were compared among wild-type, APP/PS1 and CART-treated APP/PS1 mice. The mRNA and protein expression levels of Aβ metabolism-associated enzymes, including neprilysin (NEP), insulin-degrading enzyme (IDE), receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP-1), in the hippocampus were measured via reverse transcription-quantitative PCR and western blotting, respectively. CART improved the memory impairment of APP/PS1 mice by reducing oxidative stress, inhibiting DNA damage and protecting against mitochondrial dysfunction in the cerebral cortex and hippocampus. CART also reduced cell senescence and oxidative stress in Aβ1-42-exposed primary cortical neurons in APP/PS1 mice. Moreover, CART promoted Aβ degradation via modulating Aβ metabolism-associated enzymes, including IDE, NEP, LRP-1 and RAGE. Collectively, the present study indicated that CART improved the learning and memory capacity of APP/PS mice, thus may have potential to serve as a novel therapeutic agent for AD.

Telomeric alterations in the default mode network during the progression of Alzheimer's disease: Selective vulnerability of the precuneus.

Although telomere length (TL) and telomere maintenance proteins (shelterins) are markers of cellular senescence and peripheral blood biomarkers of Alzheimer's disease (AD), little information is available on telomeric alterations during the prodromal stage (MCI) of AD. We investigated TL in the default mode network (DMN), which underlies episodic memory deficits in AD, as well as shelterin protein and mRNA levels in the precuneus (PreC). Telomere length was evaluated in DMN hubs and visual cortex using quantitative PCR (qPCR). In the PreC, western blotting and NanoString nCounter expression analyses evaluated shelterin protein and mRNA levels, respectively, in cases with an antemortem clinical diagnosis of no cognitive impairment (NCI), MCI and AD. TL was significantly reduced in the PreC in MCI and AD compared to NCI, but stable in frontal, inferior temporal, posterior cingulate and visual cortex. PreC TL correlated significantly with performance on cognitive tests. NCI cases with high vs low Braak scores displayed significantly shorter TL in posterior cingulate and frontal cortex, which correlated significantly with neuritic and diffuse amyloid-β plaque counts. Shelterin protein levels (TIN2, TRF1, TRF2 and POT1) declined in MCI and AD compared to NCI. The PreC displayed stable expression of shelterins TERF1, TERF2, POT1, RAP1 and TPP1, while TINF2 mRNA significantly increased in AD compared to NCI. These findings indicate a selective vulnerability to telomere attrition within different nodes of the DMN in prodromal AD and in aged NCI individuals with high Braak scores highlighting a putative role in the pathogenesis of AD.

Visual mental imagery in mild cognitive impairment: A pilot study

AbstractBackgroundVisual Mental Imagery (VMI), the ability of seeing with the mind eyes, has shown to be related with autobiographical memory deficits inAlzheimer's disease (AD) (El Haj et al., 2019). Hippocampus, affected by AD neuropathology since early stages, plays a pivotal contribution to the recollection of previous memories in service of VMI; however, little is known about VMI in Mild Cognitive Impairment (MCI). Basing on the current model of VMI and findings that the various processes and contents of VMI decline differently in physiological ageing (Piccardi et al. 2015), we investigated whether VMI is involved by MCI analyzing which processes and specific contents are compromised to evaluate the possible role of deficit in VMI as early neuropsychological marker of dementia.MethodTwelve amnestic‐MCI patients (mean age = 75.42, SD = 5.68; mean education=10.92, SD=4.17) and eleven healthy controls (HC) (mean age = 71.09, DS = 8.40; mean education = 13.18, SD = 4.64), matched for Age and Education, were enrolled. VMI was extensively assessed in all patients and controls by means of 1) an adapted version of The Complete Visual Mental Imagery Battery (CVMIB; Palermo et al., 2016), including tasks evaluating the generation, maintenance, inspection and transformation of different types of visual mental images (i.e. objects, buildings and faces), and 2) the O’Clock test (Grossi et al.,1994) that allows to disentangle the possible role of perceptive difficulties in the VMI task’s performance.ResultParametric and non‐parametric analyses revealed that MCI performed worse than HC in all CVMIB’s tasks except transformation (i.e. Mental Rotation and Folding tasks) and for the generation of VMI of faces. VMI deficits seem not attributable to perceptual difficulties due to the absence of deficits in the Perceptive task of the O’Clock Test (see Figure 1).ConclusionPresent preliminary results suggest that VMI is impaired since the early phase of cognitive decline and an extensive assessment of VMI, taking into account the different components and contents of VMI, may be used to better characterize MCI neuropsychological profile as well as early neuropsychological marker of dementia.

MiR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aβ1-42-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.

Riluzole ameliorates soluble Aβ1–42-induced impairments in spatial memory by modulating the glutamatergic/GABAergic balance in the dentate gyrus

Soluble amyloid beta (Aβ) is believed to contribute to cognitive deficits in the early stages of Alzheimer's disease (AD). Increased soluble Aβ1–42 in the hippocampus is closely correlated with spatial learning and memory deficits in AD. Riluzole (RLZ), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), has beneficial effects for AD. However, the mechanism underlying the effects remains unclear. In this study, its neuroprotective effect against soluble Aβ1–42-induced spatial cognitive deficits in rats was assessed. We found that intrahippocampal injection of soluble Aβ1–42 impaired spatial cognitive function and suppressed long-term potentiation (LTP) of the DG region, which was relevant to soluble Aβ1–42-induced shift of the hippocampal excitation/inhibition balance toward excitation. Interestingly, RLZ ameliorated Aβ1–42-induced behavioral and LTP impairments through rescuing the soluble Aβ1–42-induced excitation/inhibition imbalance. RLZ attenuated Aβ1–42-mediated facilitation of excitatory synaptic transmission by facilitating glutamate reuptake and decreasing presynaptic glutamate release. Meanwhile, RLZ attenuated the suppression of inhibitory synaptic transmission caused by Aβ1–42 by potentiating postsynaptic GABA receptor function. These results suggest that RLZ exerts a neuroprotective effect against soluble Aβ1–42-related spatial cognitive deficits through rescuing the excitation/inhibition imbalance, and it could be a potential therapy for AD.

Yeast beta-Glucan effects on gut microbiota for regulating insulin signaling system on alzheimer's disease

AbstractIntroduction:Alzheimer's disease (AD) is a progressive neurodegenerative disease for dementia in adults. The main pathological alterations are extracellular senile plaque deposits, intracellular neurofibrillary tangles and neuronal apoptosis. Recent researches indicated that T2D is closely with AD by insulin resistance in central nerves system progression. Nevertheless, the pathological mechanism remains unclear and treatment is limited. β-glucan extracted from yeast, as a dietary fiber with high bioactivity, edible, good taste and easy-obtainable, have been showed abilities such as anti-diabetic, anti-inflammatory and prebiotic. Based on this, β-glucan can reduce insulin resistance and maintain gut microbiota thereby alleviating lesions of early AD.Materials and Methods:In this study, we used 36 male wild-type C57BL/6J mice were divided to 3 groups (control (C) mice injected i.c.v. with 0.9% saline as a vehicle, mice injected i.c.v. with Aβ1–42 (Aβ1–42 group), mice injected with Aβ1–42 and soluble yeast β-glucan 100 mg/kg body weight by oral gavage daily (o.g.) for 5 wks (Aβ1–42 + Glu)). H&E method was detected for structure of hippocampus. Morris water maze test was performed to assess the cognitive performance of Aβ-infusion mice. The microbiota composition was analyzed by 16sRNA sequencing. The levels of inflammatory were measured in hippocampal and plasma by Meso-scale Discovery (MSD). Western blot was performed to detect the level of protein in insulin signaling pathway. One-way ANNOVA with Student-Newman-Keuls was applied for the data analysis through SPSS software version 22.0.Results:As demonstrated by H&E sections, β-glucan reduced neuron damage in AD mice hippocampus. Decreased the levels of Aβ and phosphorylation of Tau protein expression in hippocampus (P < 0.05) and ameliorated insulin resistance (p-IRS-1) in hippocampus (P < 0.05). According by results from MSD and Western-blot that showed TNF-α (P < 0.05), phosphorylated JNK (P < 0.01) and Tau were up-regulated in AD but β-glucan group decreased. In addition, the abundance of beneficial bacteria in β-glucan mice is increased (g_Alistipes, g_Rikeenella and g_Saccharibecteria genera incerae sedies).Discussion:Summary, this study illustrated that β-glucan regulated insulin signaling for ameliorating learning and memory deficit in AD. Due to β-glucan can not pass Blood-Brain-Barrier, we hypothesized that β-glucan could regulates gut microbiota by metabolites for ameliorating neuron damage. Our study provides new ideas for the prevention of AD.

Harnessing neurogenesis in the adult brain-A role in type 2 diabetes mellitus and Alzheimer's disease.

Some metabolic disorders, such as type 2 diabetes mellitus (T2DM) are risk factors for the development of cognitive deficits and Alzheimer's disease (AD). Epidemiological studies suggest that in people with T2DM, the risk of developing dementia is 2.5 times higher than that in the non-diabetic population. The signaling pathways that underlie the increased risk and facilitate cognitive deficits are not fully understood. In fact, the cause of memory deficits in AD is not fully elucidated. The dentate gyrus of the hippocampus plays an important role in memory formation. Hippocampal neurogenesis is the generation of new neurons and glia in the adult brain throughout life. New neurons incorporate in the granular cell layer of the dentate gyrus and play a role in learning and memory and hippocampal plasticity. A large body of studies suggests that hippocampal neurogenesis is impaired in mouse models of AD and T2DM. Recent evidence shows that hippocampal neurogenesis is also impaired in human patients exhibiting mild cognitive impairment or AD. This review discusses the role of hippocampal neurogenesis in the development of cognitive deficits and AD, and considers inflammatory and endothelial signaling pathways in T2DM that may compromise hippocampal neurogenesis and cognitive function, leading to AD.

Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease.

The hippocampus is one of the most affected areas in Alzheimer's disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.

Spotlight on the February 20 issue

#### Notable in Neurology this week This issue features an article that discusses the contribution of electrophysiologic testing to the diagnosis and anatomic classification of myoclonus; another determines the relationships among white matter hyperintensities, temporal lobe atrophy, and verbal memory deficits in Alzheimer disease. A featured article explores brain and cervical cord changes in patients with amyotrophic lateral sclerosis due to SOD1 mutation. ### Adjunct zonisamide to levodopa for DLB parkinsonism: A randomized double-blind phase 2 study Although levodopa is considered the standard therapy for parkinsonism, a core clinical feature of dementia with Lewy bodies (DLB), …