Pathological Features Of Alzheimer's Disease Research Articles

Neuroprotective Effects of Macrovipera lebetina Snake Venom in the Model of Alzheimer’s Disease

Pathological features of Alzheimer’s disease (AD) include accumulation and deposition of β-amyloid (Aβ) in the brain, activation of astrocytes and microglia, and disruption of cholinergic neurotransmission. In our experiments on rats, a model of AD was created by intracerebroventricular (i.c.v.) injections of Aβ25–35 amyloid. In another animal group, this was combined with intramuscular (i.m.) injections of small doses of Macrovipera lebetina (ML) snake venom (50 μl of 5% solution of an LD50 dose per animal seven times with one-day-long intervals). In the AD model, the most vulnerable neurons were found in the hippocampal fields CA1 and CA3. The phosphatase activity in the hippocampus of Aβ-injected rats sharply dropped. Systemic administration of small doses of ML venom induced positive changes in the structural characteristics of hippocampal neurons, increased the density of neurons in the above fields, normalized metabolism, and intensified Ca2+-dependent phosphorylation. Under the action of ML venom, the proportion of responses of hippocampal pyramidal neurons after high-frequency tetanic stimulation of the ipsilateral entorhinal cortex in the form of tetanic depression–posttetanic potentiation increased, and an overall increase in the firing rate of hippocampal neurons was observed. The intensity of free radical processes in some tissues of Aβ-affected animals became much lower under the action of ML venom. Thus, small doses of this venom manifest clear neuroprotective effects in the rat AD model.

Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study.

The association between the pathological features of AD and dementia is stronger in younger old persons than in older old persons suggesting that additional factors are involved in the clinical expression of dementia in the oldest old. Cumulative data suggests that neuroinflammation plays a prominent role in Alzheimer's disease (AD) and different studies reported an age-associated dysregulation of the neuroimmune system. Consequently, we sought to characterize the pattern of microglial cell activation and astrogliosis in brain post mortem tissue of pathologically confirmed cases of early and late onset AD (EOAD and LOAD) and determine their relation to age. Immunohistochemistry (CD68 and glial fibrillary acidic protein) with morphometric analysis of astroglial profiles in 36 cases of AD and 28 similarly aged controls. Both EOAD and LOAD groups had higher microglial scores in CA1, entorhinal and temporal cortices, and higher astroglial response in CA1, dentate gyrus, entorhinal and temporal cortices, compared to aged matched controls. Additionally, EOAD had higher microglial scores in subiculum, entorhinal and temporal subcortical white matter, and LOAD higher astrogliosis in CA2 region. Overall, we found that the neuroinflammatory pathological markers in late stage AD human tissue to have a similar pattern in both EOAD and LOAD, though the severity of the pathological markers in the younger group was higher. Understanding the age effect in AD will be important when testing modifying agents that act on the neuroinflammation.

Amyloid-β Derived from the Brain of the Alzheimer's Disease Transgenic Mouse Is Resistant to Proteolytic Digestion Due to Its Conformation.

The main pathological feature of Alzheimer's disease (AD) is the formation of abundant amyloid-β (Aβ) plaques in the human brain. Studies have reported that Aβ from the AD brain is resistant to proteolytic digestion, which may explain why Aβ cannot be readily eliminated from this organ. However, there are only a few studies that address this important question. We used the AD transgenic mouse (APP/PS1) model to show that Aβ derived from the brain of the old mouse is resistant to proteolytic digestion. This was in contrast to the proteinase K-sensitive human Aβ peptide, whose amino acid sequence was identical to that of AD mouse-derived Aβ but whose conformation was different (i.e., the native protein, but not the peptide, folded into a three-dimensional conformation). To address this question, we denatured AD mouse-derived Aβ with urea and found that Aβ became proteinase K-sensitive. This phenomenon was concentration-dependent, and these results were confirmed by another protein denaturant, guanidinium hydrochloride. We recovered the conformation of the denatured AD mouse-derived Aβ by eliminating urea and adding the human Aβ peptide, and we found that human Aβ was converted to the proteinase K-resistant form in the presence of partially undenatured AD mouse-derived Aβ. However, upon the addition of the rat Aβ peptide, there were no Aβ proteinase K-resistant fragments. Our results show that the resistance of AD mouse-derived Aβ to proteolytic digestion is dependent on the three-dimensional conformation of Aβ. In summary, this study provides new insights on why Aβ plaques fail to be degraded in the human brain.

Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer's Disease: Testosterone as a Modifier.

Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal aging, and although there is no significant increase in cerebral Aβ deposition in T2DM, the extent of Aβ accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk.

COMORBIDITIES IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT WERE NOT RELATED TO AD PATHOLOGY ACCORDING TO CEREBROSPINAL FLUID BIOMARKERS

It is not clear whether comorbidities may have any influence over the pathological features of Alzheimer's disease (AD) detected in the cerebrospinal fluid in patients with mild cognitive impairment (MCI). We have a group of patients who met the criteria diagnoses for MCI who underwent several tests and most of them had comorbidities. We investigated 72 individuals with MCI that were submitted to the analyses of cerebrospinal fluid (CSF) for identification of AD pathology. 30 of them had the cumulative illness rating scale registered (from zero when there is no pathology to 56 when there is severe impairment of 14 different systems). Those 30 patients were divided into two groups: 8 patients with Aβ1–42/Ptau ratio <9.53 to establish the cut-off as a reference for AD pathology and 22 with the ratio >9.53 (without AD pathology). The first group had an average of 16.62 points in the CIRS (variation was from 14 to 21). The second group had average of 16.59 in the CIRS (variation from 1 to 23). Both groups had similar scores for comorbidities (CIRS). Correlations were not statistically significant (p>0.5). We also paired both groups with Fazekas scale; in the first group the average of Fazekas was 1.60 and in the second group, 1.42. Correlations also were not statistically significant (p>0.050). Possibly the small number of the sample was the mean limitation for the analyses. Only 30 patients had their comorbidities registered, so it was impossible to compare both groups according to the AD signature. It was also impossible to check whether white matter alterations could be caused by comorbidities, specially hypertension, diabetes and dyslipidemia. Our next step of this investigation will be to increase the sample number and verify if risk factors for dementia also are related to MCI.

Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies.

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.

Midlife Vascular Risk Factors and Late-Life Amyloid Deposition

Vascular risk factors have been associated with Alzheimer disease (AD). Extracellular amyloid plaques are one of the pathologic features of AD. To

Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach.

Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic β-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest. In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives. We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards μ-amyloid aggregation. Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study.

BackgroundThe metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain.Methods and findingsWe performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and “asymptomatic Alzheimer’s disease” (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10−8, FC = 0.52, q = 1.03 x 10−6), linolenic acid (p = 2.5 x 10−4, FC = 0.84, q = 4.03 x 10−4), docosahexaenoic acid (p = 1.7 x 10−7, FC = 1.45, q = 1.24 x 10−6), eicosapentaenoic acid (p = 4.4 x 10−4, FC = 0.16, q = 6.48 x 10−4), oleic acid (p = 3.3 x 10−7, FC = 0.34, q = 1.46 x 10−6), and arachidonic acid (p = 2.98 x 10−5, FC = 0.75, q = 7.95 x 10−5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSAConclusionsThe findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.

Uncovering the Binding and Specificity of β-Wrapins for Amyloid-β and α-Synuclein.

Amyloidogenic proteins amyloid-β peptide (Aβ) and α-synuclein (α-syn) self-assemble into fibrillar amyloid deposits, senile plaques and Lewy bodies, pathological features of Alzheimer's and Parkinson's diseases, respectively. Interestingly, a portion of Alzheimer's disease cases also exhibit aggregation of α-syn into Lewy bodies, and growing evidence also suggests that Aβ and α-syn oligomers are toxic. Therefore, the simultaneous inhibition through sequestration of the two amyloidogenic proteins may constitute a promising therapeutic strategy. Recently discovered β-wrapin proteins pave the way toward this direction as they can inhibit the aggregation and toxicity of both Aβ and α-syn. Here, we used computational methods, primarily molecular dynamics simulations and free energy calculations, to shed light into the key interaction-based commonalities leading to the dual binding properties of β-wrapins for both amyloidogenic proteins, to identify which interactions potentially act as switches diminishing β-wrapins' binding activity for Aβ/α-syn, and to examine the binding properties of the current most potent β-wrapin for Aβ. Our analysis provides insights into the distinct role of the key determinants leading to β-wrapin binding to Aβ and α-syn, and suggests that the Aβ 18VFFAED23 and α-syn 38LYVGSK43 are key domains determining the binding specificity of a β-wrapin. Our findings can potentially lead to the discovery of novel therapeutics for Alzheimer's and Parkinson's diseases.

384 - Okadaic Acid and Hypoxia Induced Dementia Model of Alzheimer’s Type in Rats

Alzheimer's disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism, animal models for the specific disease are needed. Various animal models are developed which produce one or the other AD feature but none has been known which produces full AD symptomatology. Okadaic acid (OKA) is a protein phosphatse 2A (PP2A) inhibitor which leads to hyperphosphorylation of tau protein. Hyperphosphorylated tau protein is present in intraneuronal neurofibrillary tangles, a characteristic feature of AD pathology. Intracerebroventricular (ICV) injection of OKA in rats causes neurotoxicity associated with oxidative damage and mitochondrial dysfunction. However, this model lacks amyloid pathology as observed in AD. There are compelling evidences suggesting that patients with history of stroke in which hypoxic conditions occur are more susceptible in developing AD. In this study we developed a rat model of AD by combining two different treatments, OKA and hypoxia which mimics most of the neuropathological, neurobehavioural and neurochemical changes observed in AD. In an attempt to do so, OKA, (200ng, ICV) was microinjected bilaterally into the hippocampus of male wistar rats followed by exposure of same rats to hypoxic conditions (10%) for 3 days. The combination model exhibited induction tau hyperphosphorylation along with Aβ upregulation. This induced animal model showed dysfunction in neurotransmitter system (acetylcholine activity and expression); memory impairment as assessed by morris water maze and avoidance tests along with enhanced oxidative damage. These data suggest that the OKA injection into the hippocampus of rats followed by hypoxia exposure causes amyloid beta (Aβ) upregulation, neurofibrillary tangles (NFTs) like changes, cognitive deficiency, loss of acetylcholinesterase (AChE) neurons, and oxidative stress in rats similar to that seen in AD.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aβ Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing β-amyloid (Aβ) peptide, a cleaved fragment of amyloid precursor protein (APP) via β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aβ and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aβ level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aβ and tau hyperphosphorylation.

Role of Endolysosomes in Skeletal Muscle Pathology Observed in a Cholesterol-Fed Rabbit Model of Alzheimer’s Disease

Deficits in skeletal muscles contribute not only to the functional decline in people living with Alzheimer’s disease (AD), but also to AD pathogenesis. We have shown that endolysosome dysfunction plays an important role in the development of AD pathological features in a cholesterol-fed rabbit model of AD. Interestingly we observed in skeletal muscle from the rabbit AD model increased deposition of Aβ, phosphorylated tau, and ubiquitin. Here, we tested the hypothesis that endolysosome dysfunction commonly occurs in skeletal muscle and brain in this rabbit model of AD. In skeletal muscle of rabbits fed a 2% cholesterol-enriched diet for 12 weeks we observed the presence of abnormally enlarged endolysosomes, in which were increased accumulations of free cholesterol and multiple AD marker proteins subject to misfolding and aggregation including Aβ, phosphorylated tau, and ubiquitin. Moreover, in skeletal muscle of rabbits fed the cholesterol-enriched diet we observed decreased specific activities of three different lysosome enzymes. Our results suggest that elevated levels of plasma cholesterol can disturb endolysosome structure and function as well as promote the development of AD-like pathological features in skeletal muscle and that these organellar changes might contribute to the development of skeletal muscle deficits in AD.

Fe65 Is Phosphorylated on Ser289 after UV-Induced DNA Damage.

Fe65 undergoes a phosphatase-sensitive gel mobility shift after DNA damage, consistent with protein phosphorylation. A recent study identified Ser228 as a specific site of phosphorylation, targeted by the ATM and ATR protein kinases, with phosphorylation inhibiting the Fe65-dependent transcriptional activity of the amyloid precursor protein (APP). The direct binding of Fe65 to APP not only regulates target gene expression, but also contributes to secretase-mediated processing of APP, producing cytoactive proteolytic fragments including the APP intracellular domain (AICD) and cytotoxic amyloid β (Aβ) peptides. Given that the accumulation of Aβ peptides in neural plaques is a pathological feature of Alzheimer’s disease (AD), it is essential to understand the mechanisms controlling Aβ production. This will aid in the development of potential therapeutic agents that act to limit the deleterious production of Aβ peptides. The Fe65-APP complex has transcriptional activity and the complex is regulated by multiple post-translational modifications and other protein binding partners. In the present study, we have identified Ser289 as a novel site of UV-induced phosphorylation. Interestingly, this phosphorylation was mediated by ATM, rather than ATR, and occurred independently of APP. Neither phosphorylation nor mutation of Ser289 affected the Fe65-APP interaction, though this was markedly decreased after UV treatment, with a concomitant decrease in the protein levels of APP in cells. Using mutagenesis, we demonstrated that Fe65 Ser289 phosphorylation did not affect the transcriptional activity of the Fe65-APP complex, in contrast to the previously described Ser228 site.

Targeting microglia for the treatment of Alzheimer's Disease.

While histological changes in microglia have long been recognized as a pathological feature of Alzheimer's disease (AD), recent genetic association studies have also strongly implicated microglia in the etiology of the disease. Coding and noncoding polymorphisms in several genes expressed in microglia-including APOE, TREM2, CD33, GRN, and IL1RAP-alter AD risk, and therefore could be considered as entry points for therapeutic intervention. Furthermore, microglia may have a substantial effect on current amyloid β (Aβ) and tau immunotherapy approaches, since they are the primary cell type in the brain to mediate Fc receptor-facilitated antibody effector function. In this review, we discuss the considerations in selecting microglial therapeutic targets from the perspective of drug discovery feasibility, and consider the role of microglia in ongoing immunotherapy clinical strategies. GLIA 2016;64:1710-1732.

Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer's disease

Pathological features of Alzheimer's disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau. The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif‐/‐mice receiving intracerebroventricular (ICV) injection of Streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif‐/‐ mice. MIF expression and astrocyte activation were evaluated in ICV‐STZ mice using immunofluorecence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting. MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV‐STZ mice. CM from high glucose‐treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif‐/‐ astrocytes and WT astrocytes treated with the MIF inhibitor ISO‐1. ISO‐1 had no direct effect on tau phosphorylation in cultured primary neurons. These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF‐induced astrocyte activation may be useful in AD prevention and therapy.

The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice.

BackgroundAlzheimer’s disease (AD) is characterized by extracellular β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have confirmed that the activation of NgR on microglia by Nogo promotes the expression of proinflammatory cytokines and inhibits cell adhesion and migration behaviors. In the present study, we investigated the effects of Nogo/NgR signaling pathway on the pathological features of AD and possible mechanisms.MethodsAfter NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in amyloid precursor protein (APP)/PS1 transgenic mice, plaque load, tau phosphorylation, and inflammatory responses were determined. After primary mouse neurons were exposed to the conditioned medium from BV-2 microglia stimulated by Nogo, the production of Aβ and phosphorylation of tau was quantified by ELISA and western blot.ResultsInhibition of the Nogo/NgR signaling pathway ameliorated pathological features including amyloid plaques and phosphorylated levels of tau in APP/PS1 mice. In addition, after treatment with the conditioned medium from BV-2 microglia stimulated by Nogo, Aβ production and tau phosphorylation in cultured neurons were increased. The conditioned medium also increased the expression of APP, its amyloidogenic processing, and the activity of GSK3β in neurons. The conditioned medium was also proinflammatory medium, and the blockage of the Nogo/NgR pathway improved the neuroinflammatory environment in APP/PS1 mice.ConclusionsTaken together, the neuroinflammation mediated by Nogo/NgR pathway in microglia could directly take part in the pathological process of AD by influencing the amyloidogenesis and tau phosphorylation. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying the progression of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0522-x) contains supplementary material, which is available to authorized users.

The role of calsyntenin-3 in dystrophic neurite formation in Alzheimer's disease brain.

β-Amyloid (Aβ) oligomers may play an important role in the early pathogenesis of Alzheimer's disease: cognitive impairment caused by synaptic dysfunction. Dystrophic neurites surrounding Aβ plaques, another pathological feature of Alzheimer's disease, are plaque-associated neuritic alterations preceding the appearance of synaptic loss. In the present review, we focus on the mechanism of dystrophic neurite formation by Aß oligomers, and discuss the neurotoxic role of Aβ-induced calsyntenin-3 in mediating dystrophic neurite formation.

An isoform-specific role of FynT tyrosine kinase in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in old age and is characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles (NFT). Recent studies suggest that Fyn tyrosine kinase forms part of a toxic triad with β-amyloid and tau in the disease process. However, it is not known whether Fyn is associated with the pathological features of AD in an isoform-specific manner. In this study, we identified selective up-regulation of the alternative-spliced FynT isoform with no change in FynB in the AD neocortex. Furthermore, gene ontology term enrichment analyses and cell type-specific localization of FynT immunoreactivity suggest that FynT up-regulation was associated with neurofibrillary degeneration and reactive astrogliosis. Interestingly, significantly increased FynT in NFT-bearing neurons was concomitant to decreased FynB immunoreactivity, suggesting an involvement of alternative splicing in NFT formation. Furthermore, cultured cells of astrocytic origin have higher FynT to FynB ratio compared to those of neuronal origin. Lastly, primary rat mixed neuron-astrocyte cultures treated with Aβ25-35 showed selective up-regulation of FynT expression in activated astrocytes. Our findings point to an isoform-specific role of FynT in modulating neurofibrillary degeneration and reactive astrogliosis in AD. Fyn kinase is known to interact with β-amyloid and tau, and contributes to Alzheimer's disease pathogenesis. In this study, it is shown that the alternatively spliced FynT isoform is specifically up-regulated in the AD neocortex, with no change in FynB isoform. The increased FynT correlated with markers of neurofibrillary degeneration and reactive astrogliosis. In primary mixed cultures, treatment with amyloid peptides specifically up-regulated FynT in activated astrocytes. This study points to altered alternative splicing as a potential pathogenic mechanism in AD.

Standardized Herbal Formula PM012 Decreases Cognitive Impairment and Promotes Neurogenesis in the 3xTg AD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective treatment. This study investigated whether treatment with the herbal formula PM012 would improve the cognitive function and the pathological features of AD in 3xTg-AD mice. The cognitive function of 3xTg-AD mice was assessed using the Morris water maze test and positron-emission tomography (PET) with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) neuroimaging. The levels of the amyloid beta (Aβ) deposits in the hippocampus were evaluated by immunohistochemistry. Neurogenesis was assessed by quantitative labeling with the DNA marker bromodeoxyuridine (BrdU) and the newborn neuron marker doublecortin (DCX). PM012 treatment significantly ameliorated memory deficit in AD mice, as shown by shortened escape latencies and increased time spent in the target zone during probe tests. In addition, PM012 significantly decreased Aβ deposits, up-regulated the expression of brain-derived neurotrophic factor (BDNF), increased neurogenesis, and improved brain glucose metabolism in the 3xTg-AD mice. These results suggest that PM012 could be a promising treatment for AD.