Murine Model Of Alzheimer's Disease Research Articles

Roles of receptor-interacting protein kinase 1 in SH-SY5Y cells with beta amyloid-induced neurotoxicity.

Alzheimer's disease (AD), the major cause of dementia, affects the elderly population worldwide. Previous studies have shown that depletion of receptor‐interacting protein kinase 1 (RIPK1) expression reverted the AD phenotype in murine AD models. Necroptosis, executed by mixed lineage kinase domain‐like (MLKL) protein and activated by RIPK1 and RIPK3, has been shown to be involved in AD. However, the role of RIPK1 in beta‐amyloid (Aβ)‐induced necroptosis is not yet fully understood. In this study, we explored the role of RIPK1 in the SH‐SY5Y human neuroblastoma cells treated with Aβ 1–40 or Aβ 1–42. We showed that Aβ‐induced neuronal cell death was independent of apoptosis and autophagy pathways. Further analyses depicted that activation of RIPK1/MLKL‐dependant necroptosis pathway was observed in vitro. We demonstrated that inhibition of RIPK1 expression rescued the cells from Aβ‐induced neuronal cell death and ectopic expression of RIPK1 was found to enhance the stability of the endogenous APP. In summary, our findings demonstrated that Aβ can potentially drive necroptosis in an RIPK1‐MLKL‐dependent manner, proposing that RIPK1 plays an important role in the pathogenesis of AD.

TO901317 activation of LXR-dependent pathways mitigate amyloid-beta peptide-induced neurotoxicity in 3D human neural stem cell culture scaffolds and AD mice

Alzheimer's disease (AD) is the major cause of neurodegeneration worldwide and is characterized by the accumulation of amyloid beta (Aβ) in the brain, which is associated with neuronal loss and cognitive impairment. Liver X receptor (LXR), a critical nuclear receptor, and major regulator in lipid metabolism and inflammation, is suggested to play a protective role against the mitochondrial dysfunction noted in AD. In our study, our established 3D gelatin scaffold model and a well characterized in vivo (APP/PS1) murine model of AD were used to directly investigate the molecular, biochemical and behavioral effects of neuronal stem cell exposure to Aβ to improve understanding of the in vivo etiology of AD. Herein, human neural stem cells (hNSCs) in our 3D model were exposed to Aβ, and had significantly decreased cell viability, which correlated with decreased mRNA and protein expression of LXR, Bcl-2, CREB, PGC1α, NRF-1, and Tfam, and increased caspase 3 and 9 activities. Cotreatment with a synthetic agonist of LXR (TO901317) significantly abrogated these Aβ-mediated effects in hNSCs. Moreover, TO901317 cotreatment both significantly rescues hNSCs from Aβ-mediated decreases in ATP levels and mitochondrial mass, and significantly restores Aβ-induced fragmented mitochondria to almost normal morphology. TO901317 cotreatment also decreases tau aggregates in Aβ-treated hNSCs. Importantly, TO901317 treatment significantly alleviates the impairment of memory, decreases Aβ aggregates and increases proteasome activity in APP/PS1 mice; whereas, these effects were blocked by cotreatment with an LXR antagonist (GSK2033). Together, these novel results improve our mechanistic understanding of the central role of LXR in Aβ-mediated hNSC dysfunction. We also provide preclinical data unveiling the protective effects of using an LXR-dependent agonist, TO901317, to block the toxicity observed in Aβ-exposed hNSCs, which may guide future treatment strategies to slow or prevent neurodegeneration in some AD patients.

Modulation of cGAS-STING Pathway by Nicotinamide Riboside in Alzheimer's Disease.

Numerous studies demonstrate a global decrease in nicotinamide adenine dinucleotide (NAD+) with aging. This decline is associated with the development of several of the hallmarks of aging such as reduced mitophagy and neuroinflammation, processes thought to play a significant role in the progression of Alzheimer's disease (AD). Augmentation of NAD+ by oral administration of a precursor, nicotinamide riboside (NR), reduces senescence of affected cells, attenuates DNA damage and neuroinflammation in the transgenic APP/PS1 murine model of AD. Inflammation mediated by microglial cells plays an important role in progression of AD and other neurodegenerative diseases. The cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) and downstream stimulator of interferon genes (STING), generates an interferon signature characteristic of senescence and inflammaging in the brain of AD mice. Elevated cGAS-STING observed in the AD mouse brains and human AD fibroblasts was normalized by NR. This intervention also increased mitophagy with improved cognition and behavior in the APP/PS1 mice. These studies suggest that modulation of the cGAS-STING pathway may benefit AD patients and possibly other disorders characterized by compromised mitophagy and excessive neuroinflammation.

Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach.

Alzheimer's disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer's disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells. The presence of the inflammasomes such as nucleotide-binding leucine-rich repeat receptors protein 1 in neurons accelerates amyloid-beta -induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine Alzheimer's disease models. However, the pathways involved in amyloid-beta activation of inflammasomes have yet to be elucidated. In this study, a gene trap mutagenesis approach was utilised to resolve the genes functionally involved in inflammasome signalling within neurons, and the mechanism behind amyloid-beta-induced neuronal death. The results indicate that amyloid-beta significantly accelerated neuroinflammatory cell death in the presence of a primed inflammasome (the NLR family pyrin domain-containing 1). The mutagenesis screen discovered the atypical mitochondrial Ras homolog family member T1 as a significant contributor to amyloid-beta-induced inflammasome -mediated neuronal death. The mutagenesis screen also identified two genes involved in transforming growth factor beta signalling, namely Transforming Growth Factor Beta Receptor 1 and SNW domain containing 1. Additionally, a gene associated with cytoskeletal reorganisation, SLIT-ROBO Rho GTPase Activating Protein 3 was found to be neuroprotective. In conclusion, these genes could play important roles in inflammasome signalling in neurons, which makes them promising therapeutic targets for future drug development against neuroinflammation in Alzheimer's disease.

Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

Alzheimer’s disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. In AD, a distorted brain redox homeostasis and complexation by amyloid-beta and hyperphosphorylated tau may alter the isotopic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the homeostasis of these elements. We used inductively coupled plasma–mass spectrometry (ICP-MS)-based techniques to determine the total Cu, Fe, and Zn contents in the brain, as well as their isotopic compositions in both mouse brain and serum. Results for male transgenic tau (Line 66, L66) and amyloid/presenilin (5xFAD) mice were compared with those for the corresponding age- and sex-matched wild-type control mice (WT). Our data show that L66 brains showed significantly higher Fe levels than did those from the corresponding WT. Significantly less Cu, but more Zn was found in 5xFAD brains. We observed significantly lighter isotopic compositions of Fe (enrichment in the lighter isotopes) in the brain and serum of L66 mice compared with WT. For 5xFAD mice, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu. Our findings indicate significant pathology-specific alterations of Fe and Zn brain homeostasis in mouse models of AD. The associated changes in isotopic composition may serve as a marker for proteinopathies underlying AD and other types of dementia.

Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD

IntroductionThe accumulation of oxidative stress, neuroinflammation and abnormal aggregation of amyloid β-peptide (Aβ) have been shown to induce synaptic dysfunction and memory deficits in Alzheimer's disease (AD). Cellular depletion of the major endogenous antioxidant Glutathione (GSH) has been linked to cognitive decline and the development of AD pathology. Supplementation with γ-glutamylcysteine (γ-GC), the immediate precursor and the limiting substrate for GSH biosynthesis, can transiently augment cellular GSH levels by bypassing the regulation of GSH homeostasis. MethodsIn the present study, we investigated the effect of dietary supplementation of γ-GC on oxidative stress and Aβ pathology in the brains of APP/PS1 mice. The APP/PS1 mice were fed γ-GC from 3 months of age with biomarkers of apoptosis and cell death, oxidative stress, neuroinflammation and Aβ load being assessed at 6 months of age. ResultsOur data showed that supplementation with γ-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptosis, increased both total GSH and the glutathione/glutathione disulphide (GSH/GSSG) ratio and replenished ATP and the activities of the antioxidant enzymes (superoxide dismutase (SOD), catalase, glutamine synthetase and glutathione peroxidase (GPX)), the latter being a key regulator of ferroptosis. Brain Aβ load was lower and acetylcholinesterase (AChE) activity was markedly improved compared to APP/PS1 mice fed a standard chow diet. Alteration in brain cytokine levels and matrix metalloproteinase enzymes MMP-2 and MMP-9 suggested that γ-GC may lower inflammation and enhance Aβ plaque clearance in vivo. Spatial memory was also improved by γ-GC as determined using the Morris water maze. ConclusionOur data collectively suggested that supplementation with γ-GC may represent a novel strategy for the treatment and/or prevention of cognitive impairment and neurodegeneration.

Intermittent hypoxia improves cognition and reduces anxiety-related behavior in APP/PS1 mice.

IntroductionAlthough hypoxia can exacerbate symptoms of various neurological disorders, accumulating evidence has indicated that intermittent hypoxia (IH) may exert protective effects against brain diseases. In the present study, we aimed to determine whether exposure to IH exerts beneficial effects in a transgenic murine model of Alzheimer's disease (AD). Because comorbid anxiety is prevalent among patients with AD, we explored the effects of IH on anxiety‐like behaviors and associated factors in APP/PS1 mice.MethodsAPP/PS1 mice were subjected to IH for two weeks. We assessed cognitive performance and anxiety‐related behavior using standard behavioral assessments. Amyloid beta (Aβ) levels in the hippocampus were assessed using immunofluorescence and enzyme‐linked immunosorbent assays (ELISA). We also assessed cell morphology and brain‐derived neurotrophic factor (BDNF) expression in the hippocampus.ResultsExposure to IH significantly increased cognitive performance and decreased anxiety‐related behaviors in APP/PS1 mice. Immunofluorescence and ELISA results revealed that IH pretreatment significantly lowered Aβ levels in the cortex and hippocampus. Morphological studies validated the neuroprotective effect of IH exposure on hippocampal neurogenesis. Molecular studies revealed IH‐enhanced BDNF expression and inhibition of apoptosis‐related protein expression in the hippocampus of APP/PS1 mice.ConclusionsOur study demonstrates that IH improves cognition and reduces anxiety in a murine model of AD. Thus, further studies are required to determine whether IH can be used as a preventive/adjuvant therapy in patients with AD.

Oral Monosodium Glutamate Administration Causes Early Onset of Alzheimer's Disease-Like Pathophysiology in APP/PS1 Mice.

Glutamate excitotoxicity has long been related to Alzheimer's disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aβ and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, we observed a decrease in the AMPA receptor subunit GluA1 and they had impaired long-term potentiation. The Hebb-Williams Maze revealed that they had memory deficits. We show here for the first time that oral MSG supplementation can accelerate AD-like pathophysiology in a mouse model of AD.

PROTEOLIPIDOME ANALYSIS OF HIPPOCAMPAL TISSUE FROM A MURINE ALZHEIMER’S DISEASE MODEL TO FACILITATE THERAPEUTIC TARGET IDENTIFICATION

Mass spectrometry-based proteomics has potential for uncovering the molecular mechanisms underlying Alzheimer's Disease (AD). However, proteins with atypical biochemical/biophysical properties may go understudied as they may not survive the typical proteomics workflow. Utilizing a unique approach, we have assessed differences across the proteolipidome between the E4FAD murine model of AD and wildtype mice. A liquid-liquid extraction adapted from the Bligh and Dyer method [J. Biochem. Physiol. 1959] was used to isolate proteolipids from hippocampal tissue from apoliprotein E4-5XFAD transgenic and wild-type C57BL/6 mice. Proteolipids were digested with trypsin, labeled with isobaric tandem mass tags (TMT) to provide relative quantitation. Peptides were injected onto a laser-pulled nanobore C18 column and resolved on a liquid chromatograph using an optimized 3-hour gradient coupled to a hybrid quadrupole-Orbitrap mass spectrometer operating in the dd-MS2 mode. Relative peptide abundance was determined using a Proteome Discoverer 2.2. Proteins with a p-value ≤ 0.05 that exhibited a log2-fold change of 0.5 or greater were subjected to functional protein association network analysis as well as comprehensive gene set enrichment analysis. By comparison with results obtained using an optimized bottom-up proteomics workflow, it is evident that many of the proteins found in this experiment are unique to this technique and do not appear in experiments using standard detergent-based aqueous extraction buffers. The relative abundance of many proteins differed between E4FAD and wildtype hippocampi and Protein Center gene ontology analysis revealed numerous proteins to be membrane-specific with protein binding functions. Additionally, many proteins had post-translational modifications (PTMs) such as phosphorylation and acetylation, revealing an interconnected signaling network of proteins that differ in wildtype and E4FAD hippocampus. This novel approach analyzing organically extracted proteolipid fractions provides supplemental coverage of the proteome not revealed by conventional proteomics workflows, including changes in protein expression and PTMs distinctive for the E4FAD as compared to wildtype mice. This method has provided new information regarding the pathological mechanisms in this model, and will be used to facilitate identification of new targets for potential therapeutic development in the treatment of AD.

Apamin Improves Prefrontal Nicotinic Impairment in Mouse Model of Alzheimer’s Disease

Disruption of attention is an early and disabling symptom of Alzheimer's disease (AD). The underlying cellular mechanisms are poorly understood and treatment options for patients are limited. These early attention deficits are evident in the TgCRND8 mouse, a well-established murine model of AD that recapitulates several features of the disease. Here, we report severe impairment of the nicotinic receptor-mediated excitation of prefrontal attentional circuitry in TgCRND8 mice relative to wild-type littermate controls. We demonstrate that this impairment can be remedied by apamin, a bee venom neurotoxin peptide that acts as a selective antagonist to the SK family of calcium-sensitive potassium channels. We probe this seeming upregulation of calcium-sensitive inhibition and find that the attenuated nicotinic firing rates in TgCRND8 attention circuits are mediated neither by greater cellular calcium signals nor by elevated SK channel expression. Instead, we find that TgCRND8 mice show enhanced functional coupling of nicotinic calcium signals to inhibition. This SK-mediated inhibition exerts a powerful negative feedback on nicotinic excitation, dampening attention-relevant signaling in the TgCRND8 brain. These mechanistic findings identify a new cellular target involved in the modulation of attention and a novel therapeutic target for early attention deficits in AD.

The Role of Neuronal NLRP1 Inflammasome in Alzheimer's Disease: Bringing Neurons into the Neuroinflammation Game.

The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates, and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β (IL-1β) and interleukin-18 (IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the Nlrp1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD.

The NAAG'ing Concerns of Modeling Human Alzheimer's Disease in Mice.

Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer's disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R)

While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and noninvasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer's disease (AD), and Parkinson's disease, among others. We have developed [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain. [11C]CPPC demonstrates high and specific brain uptake in a murine and nonhuman primate lipopolysaccharide model of neuroinflammation. It also shows specific and elevated uptake in a murine model of AD, experimental allergic encephalomyelitis murine model of demyelination and in postmortem brain tissue of patients with AD. Radiation dosimetry in mice indicated [11C]CPPC to be safe for future human studies. [11C]CPPC can be synthesized in sufficient radiochemical yield, purity, and specific radioactivity and possesses binding specificity in relevant models that indicate potential for human PET imaging of CSF1R and the microglial component of neuroinflammation.

The Emerging Role of Altered Cerebellar Synaptic Processing in Alzheimer's Disease.

The role of the cerebellum in Alzheimer’s disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-β (Aβ) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aβ-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aβ toxic damage, even at the early stage of the disease, with consequences on motor performance.

NORMALIZATION OF HIPPOCAMPAL SIRTUIN 1 LEVELS IN A MURINE APOLIPOPROTEIN E4-5XFAD MODEL OF AD RESTORES COGNITIVE FUNCTION

Decreases in the level of major longevity determinant sirtuin 1 (SirT1) have been associated with Alzheimer's Disease (AD) and expression of a major genetic risk factor for sporadic AD, apolipoprotein E4 (ApoE4) [Kumar et al. 2013 PLoS One 8(4):e61560; Theendakara et al. 2013 PNAS 110(45):18303]. We previously identified a compound - A03 - that normalized SirT1 levels in the presence of ApoE4 in vitro. Here, we determined A03’s efficacy in enhancing SirT1 in brain and improving memory in vivo in a murine model of AD wherein human targeted-replacement ApoE4 (huApoE4 TR) is expressed in the 5XFAD model of AD (E4FAD). E4FAD mice expressing huApoE4 TR and human amyloid precursor protein (huAPP) with three mutations (K670N/M671L; I716V; & V717I) and human presenilin 1 (PS1) with two mutations (M146L & L286V) received 20 mg/kg A03 BID for a total dose of 40 mg/kg/day by the oral route for 56 days. Vehicle-only E4FAD and vehicle-only aged-matched (9-12 mo) non-transgenic (NTg) groups were used as controls. Working object and spatial memory were assessed using the Novel Object Recognition (NOR) and Novel Location Recognition (NLR) testing paradigms, respectively, both pre- and end-study. Levels of sirtuin 1 and soluble amyloid precursor protein alpha (sAPPα) were determined in hippocampi and frontal cortices of all mice using custom AlphaLISAs (Perkin-Elmer), and amyloid-beta (Aβ) 1-40 and 1-42 were determined by ELISA (Thermo). A03 was found to be orally available and brain-penetrant, and 56-day oral treatment significantly increased SirT1 in the hippocampi of E4FAD mice as compared to vehicle-treated E4FAD mice. A03 treatment of E4FAD mice also improved working object memory in NOR (novelty preference) significantly as compared to E4FAD vehicle-treated controls.

Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer's Disease in Humans.

There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer's disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans. We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls. Structural and resting state functional MRI scans, and neuropsychological scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested. VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD. Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration.

Mitochondrial Molecular Abnormalities Revealed by Proteomic Analysis of Hippocampal Organelles of Mice Triple Transgenic for Alzheimer Disease.

Mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD). However, the precise mitochondrial molecular deficits in AD remain poorly understood. Mitochondrial and nuclear proteomic analysis in mature male triple transgenic AD mice (PS1M146V/APPSwe/TauP301L) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-MS/MS, bio-informatics analysis and immunofluorescent staining were performed in this study. In addition to impaired spatial memory impairment and intracellular accumulation of amyloid 1–42 (Aβ1–42) in the 3xTg-AD mice, a well-accepted mouse model of the human disease, we also found significantly increased DNA oxidative damage in entorhinal cortex, hippocampal CA1, CA3 and dental gyrus (DG), as evidenced by the positive staining of 8-hydroxyguanosine, a biomarker of mild cognitive impairment early in AD. We identified significant differences in 27 hippocampal mitochondrial proteins (11 increased and 16 decreased), and 37 hippocampal nuclear proteins (12 increased and 25 decreased) in 3xTg-AD mice compared with the wild-type (WT) mice. Differentially expressed mitochondrial and nuclear proteins were mainly involved in energy metabolism (>55%), synapses, DNA damage, apoptosis and oxidative stress. Two proteins were differentially expressed in both hippocampal mitochondria and nuclei, namely electron transport chain (ETC)-related protein ATP synthase subunit d (ATP5H) was significantly decreased, and apoptosis-related dynamin-1 (DYN1), a pre-synaptic and mitochondrial division-regulated protein that was significantly increased. In sum, perturbations of hippocampus mitochondrial energy metabolism-related proteins responsible for ATP generation via oxidation phosphorylation (OXPHOS), especially nuclear-encoded OXPHOS proteins, correlated with the amyloid-associated cognitive deficits of this murine AD model. The molecular changes in respiratory chain-related proteins and DYN1 may represent novel biomarkers of AD.

Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti‐TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood–cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology. Here, we report that TNF is the main inflammatory upstream mediator in choroid plexus tissue in AD patients. This was confirmed in two murine AD models: transgenic APP/PS1 mice and intracerebroventricular (icv) AβO injection. TNFR1 contributes to the morphological damage of CPE cells in AD, and TNFR1 abrogation reduces brain inflammation and prevents blood–CSF barrier impairment. In APP/PS1 transgenic mice, TNFR1 deficiency ameliorated amyloidosis. Ultimately, genetic and pharmacological blockage of TNFR1 rescued from the induced cognitive impairments. Our data indicate that TNFR1 is a promising therapeutic target for AD treatment.

Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal Neurons.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are associated to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathologic and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-β (oAβ(1-42)). We showed that oAβ(1-42) exposure significantly decreased the density of mature (mushroom shaped) dendritic spines density and synaptic contacts number. oAβ(1-42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiology and highlight its potential as an alternative pharmacological strategy for AD.

Modeling Alzheimer's disease in progeria mice. An age-related concept.

ABSTRACTThe prevalence of Alzheimer’s disease (AD) is expected to dramatically increase in older people worldwide. Efforts to find disease-modifying treatments have been largely unsuccessful because of the focus on disease-specific pathogenesis, and lack of animal models to study AD in the context of aging and age-related co-morbidities. The geroscience approach to studying AD would suggest that modulation of aging per se would be a useful strategy, but a mammalian model system that combines both aging and AD is not available. One approach to study old age and AD is to utilize murine models of progeroid syndrome, which can provide a number of advantages not only for basic aging biology but also for preclinical drug testing. A progeria background, such as the Ercc1 mutant mouse (Ercc1−/Δ), provides an aging component not seen in current murine models of AD that lack age-related co-morbidities typical of AD patients.Ercc1−/Δ mice experience the same types of stochastic endogenous DNA damage as WT mice, but accumulate lesions faster due to impaired DNA repair, which accelerates the normal aging process by 6-fold. These mice do not show frank AD pathology but represent a predisposed or hypersensitive environment for AD pathology, where pathogenic elements of AD can be introduced, either by crossing with well-established AD transgenic mouse lines, or transcranial stereotaxic delivery directly into the brain. Since Ercc1−/Δ mice age five to six times faster than WT mice, very rapid characterization and testing of therapeutic interventions is possible. Studies are urgently needed to capitalize on the highly informative potential of this novel AD mouse model.