Dendritic Integrity Research Articles

Unraveling the Role of SSH1 in Chronic Neuropathic Pain: A Focus on LIMK1 and Cofilin Dephosphorylation in the Prefrontal Cortex.

Neuropathic pain, a debilitating condition stemming from nervous system injuries, has profound impacts on quality of life. The medial prefrontal cortex (mPFC) plays a crucial role in the modulation of pain perception and emotional response. This study explores the involvement of Slingshot Homolog 1 (SSH1) protein in neuropathic pain and related emotional and cognitive dysfunctions in a mouse model of spared nerve injury (SNI). SNI was induced in C57BL/6J mice. SSH1's role was investigated via its overexpression and knockdown using lentiviral vectors in the mPFC. Behavioral assays (thermal and mechanical allodynia, open field test, elevated plus maze, tail suspension test, Y-maze, and novel object recognition were conducted to assess pain sensitivity, anxiety, depression, and cognitive function. Tissue samples underwent Hematoxylin and Eosin staining, Western blotting, immunofluorescence, co-immunoprecipitation, and enzyme-linked immunosorbent assay for inflammatory markers. SNI mice displayed significant reductions in neuronal density and dendritic integrity in the mPFC, alongside heightened pain perception and emotional disturbances, as compared to sham controls. Overexpression of SSH1 ameliorated these alterations, improving mechanical and thermal thresholds, reducing anxiety and depressive behaviors, and enhancing cognitive performance. Conversely, SSH1 knockdown exacerbated these phenotypes. Molecular investigations revealed that SSH1 modulates pain processing and neuronal health in the mPFC partially through the dephosphorylation of Cofilin and LIM domain kinase 1 (LIMK1), as evidenced by changes in their phosphorylation states and interaction patterns. SSH1 plays a pivotal role in the modulation of neuropathic pain and associated neuropsychological disturbances in the mPFC of mice. Manipulating SSH1 expression can potentially reverse the neurophysiological and behavioral abnormalities induced by SNI, highlighting a promising therapeutic target for treating neuropathic pain and its complex comorbidities.

Neuropeptide FF Promotes Neuronal Survival and Enhances Synaptic Protein Expression Following Ischemic Injury.

This study explores the neuroprotective effects of neuropeptide FF (NPFF, FLFQPQRFamide) in the context of ischemic injury. Based on transcriptomic analysis in stroke models treated with 5-Aza-dC and task-specific training, we identified significant gene expression changes, particularly involving NPFF. To further explore NPFF's role in promoting neuronal recovery, recombinant NPFF protein (rNPFF) was used in primary mixed cortical cultures subjected to oxygen-glucose deprivation and reoxygenation. Our results demonstrated that rNPFF significantly reduced lactate dehydrogenase release, indicating decreased cellular damage. It also significantly increased the expression of TUJ1 and MAP2, markers of neuronal survival and dendritic integrity. Additionally, rNPFF significantly upregulated key synaptic proteins, including GAP43, PSD95, and synaptophysin, which are essential for synaptic repair and plasticity. Post-injury rNPFF treatment led to a significant upregulation of pro-brain-derived neurotrophic factor (BDNF) and mature BDNF, which play critical roles in neuronal survival, growth, and synaptic plasticity. Moreover, rNPFF activated the protein kinase Cε isoform, Sirtuin 1, and peroxisome proliferator-activated receptor gamma pathways, which are crucial for regulating cellular stress responses, synaptic plasticity, and energy homeostasis, further promoting neuronal survival and recovery. These findings suggest that rNPFF may play a pivotal role in enhancing neuronal survival and synaptic plasticity after ischemic injury, highlighting its potential as a therapeutic target for stroke recovery.

An MRI evaluation of white matter involvement in paradigmatic forms of spastic ataxia: results from the multi-center PROSPAX study

BackgroundAutosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Spastic Paraplegia Type 7 (SPG7) are paradigmatic spastic ataxias (SPAX) with suggested white matter (WM) involvement. Aim of this work was to thoroughly disentangle the degree of WM involvement in these conditions, evaluating both macrostructure and microstructure via the analysis of diffusion MRI (dMRI) data.Material and methodsIn this multi-center prospective study, ARSACS and SPG7 patients and Healthy Controls (HC) were enrolled, all undergoing a standardized dMRI protocol and a clinimetrics evaluation including the Scale for the Assessment and Rating of Ataxia (SARA). Differences in terms of WM volume or global microstructural WM metrics were probed, as well as the possible occurrence of a spatially defined microstructural WM involvement via voxel-wise analyses, and its correlation with patients’ clinical status.ResultsData of 37 ARSACS (M/F = 21/16; 33.4 ± 12.4 years), 37 SPG7 (M/F = 24/13; 55.7 ± 10.7 years), and 29 HC (M/F = 13/16; 42.1 ± 17.2 years) were analyzed. While in SPG7, only a mild mean microstructural damage was found compared to HC, ARSACS patients present a severe WM involvement, with a reduced global volume (p < 0.001), an alteration of all microstructural metrics (all with p < 0.001), without a spatially defined pattern of damage but with a prominent involvement of commissural fibers. Finally, in ARSACS, a correlation between microstructural damage and SARA scores was found (p = 0.004).ConclusionIn ARSACS, but not SPG7 patients, we observed a complex and multi-faced involvement of brain WM, with a clinically meaningful widespread loss of axonal and dendritic integrity, secondary demyelination and, overall, a reduction in cellularity and volume.

Cell adhesion molecule CD44 is dispensable for reactive astrocyte activation during prion disease

Prion diseases are fatal, infectious, neurodegenerative disorders resulting from accumulation of misfolded cellular prion protein in the brain. Early pathological changes during CNS prion disease also include reactive astrocyte activation with increased CD44 expression, microgliosis, as well as loss of dendritic spines and synapses. CD44 is a multifunctional cell surface adhesion and signalling molecule which is considered to play roles in astrocyte morphology and the maintenance of dendritic spine integrity and synaptic plasticity. However, the role of CD44 in prion disease was unknown. Here we used mice deficient in CD44 to determine the role of CD44 during prion disease. We show that CD44-deficient mice displayed no difference in their response to CNS prion infection when compared to wild type mice. Furthermore, the reactive astrocyte activation and microgliosis that accompanies CNS prion infection was unimpaired in the absence of CD44. Together, our data show that although CD44 expression is upregulated in reactive astrocytes during CNS prion disease, it is dispensable for astrocyte and microglial activation and the development of prion neuropathogenesis.

Extracellular vesicle encapsulated nicotinamide delivered via a trans-scleral route provides retinal ganglion cell neuroprotection

The progressive and irreversible degeneration of retinal ganglion cells (RGCs) and their axons is the major characteristic of glaucoma, a leading cause of irreversible blindness worldwide. Nicotinamide adenine dinucleotide (NAD) is a cofactor and metabolite of redox reaction critical for neuronal survival. Supplementation with nicotinamide (NAM), a precursor of NAD, can confer neuroprotective effects against glaucomatous damage caused by an age-related decline of NAD or mitochondrial dysfunction, reflecting the high metabolic activity of RGCs. However, oral supplementation of drug is relatively less efficient in terms of transmissibility to RGCs compared to direct delivery methods such as intraocular injection or delivery using subconjunctival depots. Neither method is ideal, given the risks of infection and subconjunctival scarring without novel techniques. By contrast, extracellular vesicles (EVs) have advantages as a drug delivery system with low immunogeneity and tissue interactions. We have evaluated the EV delivery of NAM as an RGC protective agent using a quantitative assessment of dendritic integrity using DiOlistics, which is confirmed to be a more sensitive measure of neuronal health in our mouse glaucoma model than the evaluation of somatic loss via the immunostaining method. NAM or NAM-loaded EVs showed a significant neuroprotective effect in the mouse retinal explant model. Furthermore, NAM-loaded EVs can penetrate the sclera once deployed in the subconjunctival space. These results confirm the feasibility of using subconjunctival injection of EVs to deliver NAM to intraocular targets.

Cdk5-dependent rapid formation and stabilization of dendritic spines by corticotropin-releasing factor

The neuropeptide corticotropin-releasing factor (CRF) exerts a pivotal role in modulating neuronal activity in the mammalian brain. The effects of CRF exhibit notable variations, depending on factors such as duration of exposure, concentration, and anatomical location. In the CA1 region of the hippocampus, the impact of CRF is dichotomous: chronic exposure to CRF impairs synapse formation and dendritic integrity, whereas brief exposure enhances synapse formation and plasticity. In the current study, we demonstrate long-term effects of acute CRF on the density and stability of mature mushroom spines ex vivo. We establish that both CRF receptors are present in this hippocampal region, and we pinpoint their precise subcellular localization within synapses by electron microscopy. Furthermore, both in vivo and ex vivo data collectively demonstrate that a transient surge of CRF in the CA1 activates the cyclin-dependent kinase 5 (Cdk5)-pathway. This activation leads to a notable augmentation in CRF-dependent spine formation. Overall, these data suggest that upon acute release of CRF in the CA1-SR synapse, both CRF-Rs can be activated and promote synaptic plasticity via activating different downstream signaling pathways, such as the Cdk5-pathway.

Exosomes Derived from M2 Microglial Cells Modulated by 1070-nm Light Improve Cognition in an Alzheimer's Disease Mouse Model.

Near-infrared photobiomodulation has been identified as a potential strategy for Alzheimer's disease (AD). However, the mechanisms underlying this therapeutic effect remain poorly characterize. Herein, it is illustrate that 1070-nm light induces the morphological alteration of microglia from an M1 to M2 phenotype that secretes exosomes, which alleviates the β-amyloid burden to improve cognitive function by ameliorating neuroinflammation and promoting neuronal dendritic spine plasticity. The results show that 4Jcm-2 1070-nm light at a 10-Hz frequency prompts microglia with an M1 inflammatory type to switch to an M2 anti-inflammatory type. This induces secretion of M2 microglial-derived exosomes containing miR-7670-3p, which targets activating transcription factor 6 (ATF6) during endoplasmic reticulum (ER) stress. Moreover, it is found that miR-7670-3p reduces ATF6 expression to further ameliorate ER stress, thus attenuating the inflammatory response and protecting dendritic spine integrity of neurons in the cortex and hippocampus of 5xFAD mice, ultimately leading to improvements in cognitive function. This study highlights the critical role of exosomes derive from 1070-nm light-modulated microglia in treating AD mice, which may provide a theoretical basis for the treatment of AD with the use of near-infrared photobiomodulation.

Brain-derived neurotrophic factor released from blood platelets prevents dendritic atrophy of lesioned adult central nervous system neurons.

In humans and other primates, blood platelets contain high concentrations of brain-derived neurotrophic factor due to the expression of the BDNF gene in megakaryocytes. By contrast, mice, typically used to investigate the impact of CNS lesions, have no demonstrable levels of brain-derived neurotrophic factor in platelets, and their megakaryocytes do not transcribe significant levels of the Bdnf gene. Here, we explore potential contributions of platelet brain-derived neurotrophic factor with two well-established CNS lesion models, using 'humanized' mice engineered to express the Bdnf gene under the control of a megakaryocyte-specific promoter. Retinal explants prepared from mice containing brain-derived neurotrophic factor in platelets were labelled using DiOlistics and the dendritic integrity of retinal ganglion cells assessed after 3 days by Sholl analysis. The results were compared with retinas of wild-type animals and with wild-type explants supplemented with saturating concentrations of brain-derived neurotrophic factor or the tropomyosin kinase B antibody agonist, ZEB85. An optic nerve crush was also performed, and the dendrites of retinal ganglion cells similarly assessed 7-day post-injury, comparing the results of mice containing brain-derived neurotrophic factor in platelets with wild-type animals. In mice engineered to contain brain-derived neurotrophic factor in platelets, the mean serum brain-derived neurotrophic factor levels were 25.74 ± 11.36 ng/mL for homozygous and 17.02 ± 6.44 ng/mL for heterozygous mice, close to those determined in primates. Retinal explants from these animals showed robust preservation of dendrite complexity, similar to that seen with wild-type explants incubated with medium supplemented with brain-derived neurotrophic factor or the tropomyosin receptor kinase B antibody agonist, ZEB85. The Sholl areas under curve were 1811 ± 258, 1776 ± 435 and 1763 ± 256 versus 1406 ± 315 in the wild-type control group (P ≤ 0.001). Retinal ganglion cell survival based on cell counts was similar in all four groups, showing ∼15% loss. A robust neuroprotective effect was also observed following optic nerve crush when assessing the dendrites of the retinal ganglion cells in the transgenic mouse, with Sholl area under the curve significantly higher compared to wild-type (2667 ± 690 and 1921 ± 392, P = 0.026), with no significant difference in the contralateral eye controls. Repeat experiments found no difference in cell survival, with both showing ∼50% loss. These results indicate that platelet brain-derived neurotrophic factor has a strong neuroprotective effect on the dendrite complexity of retinal ganglion cells in both an ex vivo and in vivo model, suggesting that platelet brain-derived neurotrophic factor is likely to be a significant neuroprotective factor in primates.

Clathrin-nanoparticles deliver BDNF to hippocampus and enhance neurogenesis, synaptogenesis and cognition in HIV/neuroAIDS mouse model

Brain derived neurotrophic factor (BDNF) promotes the growth, differentiation, maintenance and survival of neurons. These attributes make BDNF a potentially powerful therapeutic agent. However, its charge, instability in blood, and poor blood brain barrier (BBB) penetrability have impeded its development. Here, we show that engineered clathrin triskelia (CT) conjugated to BDNF (BDNF-CT) and delivered intranasally increased hippocampal BDNF concentrations 400-fold above that achieved previously with intranasal BDNF alone. We also show that BDNF-CT targeted Tropomyosin receptor kinase B (TrkB) and increased TrkB expression and downstream signaling in iTat mouse brains. Mice were induced to conditionally express neurotoxic HIV Transactivator-of-Transcription (Tat) protein that decreases BDNF. Down-regulation of BDNF is correlated with increased severity of HIV/neuroAIDS. BDNF-CT enhanced neurorestorative effects in the hippocampus including newborn cell proliferation and survival, granule cell neurogenesis, synaptogenesis and increased dendritic integrity. BDNF-CT exerted cognitive-enhancing effects by reducing Tat-induced learning and memory deficits. These results show that CT bionanoparticles efficiently deliver BDNF to the brain, making them potentially powerful tools in regenerative medicine.

High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice.

Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated. The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology. 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses. A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques. Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

Specific small-molecule inhibition of PLD1 prevents ADRD-like memory deficits by preserving dendritic spine integrity driven by amyloidogenic proteins.

Phosphatidyl choline phospholipase D (PC-PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms - a constitutively expressed PLD2 and an inducible PLD1 isoform - are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits. Synaptosomal Western blot analysis on 12 month 3xTg-AD mice hippocampi were used to investigate neuronal PLD1 expression and function. Long term potentiation of PLD1 dependent changes using pharmacological approaches in ex vivo slice preparations from wildtype and transgenic mouse models were used to assess synaptic perturbations that were first studied using the novel object recognition memory (NOR) and fear conditioning (FC) paradigms. Chronic PLD1 small molecule inhibitor treatment was assessed to ascertain the efficacy against Aβ and tau-driven AD-like memory deficit progression. Lastly, brain tissues from these animals were subjected to Western Blot analyses, Golgi analysis, immunohistochemical analysis to ascertain the potential signaling mechanism(s) that is/are perturbed/altered by overexpression of PLD1 in such diseased states. Chronic PLD1 inhibition ameliorates the synaptic dysfunction and underlying memory deficits in the 3xTg-AD mouse model by specific action on preserving mushroom spine dendritic spine integrity. Further analysis using Western Blots revealed an underlying mechanism. Using chronic administration of a well-tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory.

Assessing therapeutic potential of PLD1 inhibition in dementia: Systematic assessment of behavior, electrophysiology &amp; mechanisms of synaptic dysfunction using different parameters including sex‐specific differences

AbstractBackgroundPhosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.MethodsWe used different transgenic rodent models of AD‐like pathology and did a corroborative assessment of behavior, electrophysiology and biochemistry including western blots analysis, Golgi studies and immunofluorescence to assess the efficacy of treatment of the aberrantly elevated PLD1 levels using chronic regimen of a specific small molecule inhibitor.ResultChronic PLD1 inhibition is effective in ameliorating the synaptic dysfunction and associated memory deficits in the treated cohort compared to the age‐matched cohort. We also assessed and report sex‐specific changes in these responses that strengthen our understanding of the underlying mechanisms and brain regions that are targeted by the therapeutic approaches.ConclusionUsing chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory with an emphasis on the sex‐specific effects.

Long-term efavirenz exposure induced neuroinflammation and cognitive deficits in C57BL/6 mice

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which is widely used for anti-HIV-1. Evidences revealed that several central nervous system side effects could be observed in mice and patients with administration of EFV. However, the detailed mechanisms are still unknown. In this study, we investigated the effects of long-term EFV treatment on cognitive functions and the potential underlying mechanisms in mice. We maintained C57BL/6 mice aged 2 months with treatment containing 40 or 80 mg/kg/day EFV for 5 months, while control group treated with saline. The cognitive functions were evaluated by novel object recognition test, Barnes maze test and Morris water maze. The results showed significant short-term memory impairment in 40 and 80 mg/kg groups, and notable spatial learning and memory impairments in 80 mg/kg group, without any spontaneous activity alteration. Moreover, EFV induced impairments in dendritic integrity and synaptic plasticity in hippocampus. Furthermore, Significant increases were observed in the expression levels of pro-IL-1β, a similar tendency of TNF-α and phosphorylation of p65 of the 80 mg/kg group compared with control group. These results imply that long-term EFV treatment causes synaptic dysfunction resulting in cognitive deficits, which might be induced by the enhanced pro-inflammatory cytokines IL-1β and TNF-α via activating NF-κB pathway.

High Fat Diet Aggravates AD-Related Pathogenic Processes in APP/PS1 Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and negative lifestyle factors may contribute to its etiopathogenesis. Substantial evidence from humans and murine models reveals that Insulin Resistance (IR) associated with a high fat diet (HFD) increases the risk of developing AD and age-related amyloidogenesis. The aim of the study was to corroborate and clarify the influence of HFD on amyloidogenesis and cognitive deficits in AD model mice. We here show that a four months HFD-feeding increases IR in both the periphery and brain of APP/PS1 mice, which are used as AD models. Meanwhile, long-term HFD exacerbates cognitive defects and impairs dendritic integrity and expressions of synaptic proteins in APP/PS1 mice. Furthermore, HFD induces an increase in β-secretase (BACE1) expression and a decrease in insulin-degrading enzyme (IDE) expression, resulting in β-amyloid (Aβ) accumulation. Our data suggest that long-term HFD, with the accompanying IR, promotes Aβ toxicity and cognitive deficits, indicating that modifiable lifestyle hazards such as HFD-induced IR might contribute to AD pathogenesis.

Age-dependent ataxia and neurodegeneration caused by an \u03b1II spectrin mutation with impaired regulation of its calpain sensitivity

The neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spectrin is cleavage by calpains, a family of calcium-activated proteases. Spectrin cleavage is regulated by activated calpain, but also by the calcium-dependent binding of calmodulin (CaM) to spectrin. The physiologic significance of this balance between calpain activation and substrate-level regulation of spectrin cleavage is unknown. We report a strain of C57BL/6J mice harboring a single αII spectrin point mutation (Sptan1 c.3293G > A:p.R1098Q) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis. Homozygotes are embryonic lethal. Newborn heterozygotes of either gender appear normal, but soon develop a progressive ataxia characterized biochemically by accelerated calpain-mediated spectrin cleavage and morphologically by disruption of axonal and dendritic integrity and global neurodegeneration. Molecular modeling predicts unconstrained exposure of the mutant spectrin’s calpain-cleavage site. These results reveal the critical importance of substrate-level regulation of spectrin cleavage for the maintenance of neuronal integrity. Given that excessive activation of calpain proteases is a common feature of neurodegenerative disease and traumatic encephalopathy, we propose that damage to the spectrin MPS may contribute to the neuropathology of many disorders.

Single-neuron dynamical effects of dendritic pruning implicated in aging and neurodegeneration: towards a measure of neuronal reserve

Aging is a main risk factor for neurodegenerative disorders including Alzheimer's disease. It is often accompanied by reduced cognitive functions, gray-matter volume, and dendritic integrity. Although age-related brain structural changes have been observed across multiple scales, their functional implications remain largely unknown. Here we simulate the aging effects on neuronal morphology as dendritic pruning and characterize its dynamical implications. Utilizing a detailed computational modeling approach, we simulate the dynamics of digitally reconstructed neurons obtained from Neuromorpho.org. We show that dendritic pruning affects neuronal integrity: firing rate is reduced, causing a reduction in energy consumption, energy efficiency, and dynamic range. Pruned neurons require less energy but their function is often impaired, which can explain the diminished ability to distinguish between similar experiences (pattern separation) in older people. Our measures indicate that the resilience of neuronal dynamics is neuron-specific, heterogeneous, and strongly affected by dendritic topology and the position of the soma. Based on the emergent neuronal dynamics, we propose to classify the effects of dendritic deterioration, and put forward a topological measure of “neuronal reserve” that quantifies the resilience of neuronal dynamics to dendritic pruning. Moreover, our findings suggest that increasing dendritic excitability could partially mitigate the dynamical effects of aging.

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory.

A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP; Opa1+/−). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.

Protective effects of ischemic preconditioning against neuronal apoptosis and dendritic injury in the hippocampus are age-dependent.

Ischemic preconditioning with non-lethal ischemia can be protective against lethal forebrain ischemia. We hypothesized that aging may aggravate ischemic susceptibility and reduce brain plasticity against preconditioning. Magnetic resonance diffusion tensor imaging (DTI) is a sensitive tool to detect brain integrity and white matter architecture. This study used DTI and histopathology to investigate the effect of aging on ischemic preconditioning. In this study, adult and middle-aged male Mongolian gerbils were subjected to non-lethal 5-min forebrain ischemia (ischemic preconditioning) or sham-operation, followed by 3days of reperfusion, and then lethal 15-min forebrain ischemia. A 9.4-Tesla MR imaging system was used to study DTI indices, namely fractional anisotropy (FA), mean diffusivity (MD), and intervoxel coherence (IC) in the hippocampal CA1 and dentate gyrus (DG) areas. In situ expressions of microtubule-associated protein 2 (MAP2, dendritic marker protein) and apoptosis were also examined. The 5-min ischemia did not cause dendritic and neuronal injury and any significant change in DTI indices and MAP2 in adult and middle-aged gerbils. The 15-min ischemia-induced significant delayed neuronal apoptosis and early dendritic injury evidenced by DTI and MAP2 studies in both CA1 and DG areas with more severe injury in middle-aged gerbils than adult gerbils. Ischemic preconditioning could improve neuronal apoptosis in CA1 area and dendritic integrity in both CA1 and DG areas with better improvement in adult gerbils than middle-aged gerbils. This study thus suggests an age-dependent protective effect of ischemic preconditioning against both neuronal apoptosis and dendritic injury in hippocampus after forebrain ischemia.

Epigallocatechin-3-gallate Alleviates Cognitive Deficits in APP/PS1 Mice.

Alzheimer's disease (AD) shows cognitive impairments in clinic, which is multifactorial with different etiopathogenic mechanisms such as Aβ deposition, neuroinflammation and neuronal dystrophy involved. Therefore, multi-targets drugs with neuroprotective, anti-amyloidogenic and anti-inflammatory properties will be effective in AD treatment. Epigallocatechin-3-gallate (EGCG) possesses a broad spectrum of pharmacological activities in the prevention and treatment of multiple neurodegenerative diseases. In the present study, we showed that oral administration of EGCG (50 mg/kg) for 4 months significantly attenuated the cognitive deficits in APP/PS1 transgenic mice, which served as AD model. Moreover, EGCG induced an improvement in dendritic integrity and expression levels of synaptic proteins in the brain of APP/PS1 mice. And EGCG exerted obvious anti-inflammatory effects, which was manifested by alleviating microglia activation, decreasing pro-inflammatory cytokine (IL-1β) and increasing anti-inflammatory cytokines (IL-10, IL-13). Furthermore, β-amyloid (Aβ) plaques were markedly reduced in the hippocampus of 6-month old APP/PS1 mice after EGCG treatment. In conclusion, these findings indicate that EGCG improves AD-like cognitive impairments through neuroprotective, anti-amyloidogenic and anti-inflammatory effects, thus is a promising therapeutic candidate for AD.

Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer\u2019s disease mouse model promotes synaptic resilience

Current approaches in treatment of Alzheimer’s disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.