Brain-Derived Neurotrophic Factor Ameliorates Learning Deficits in a Rat Model of Alzheimer's Disease Induced by Aβ1-42

An emerging body of data suggests that the early onset of Alzheimer’s disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.     

Oridonin Attenuates Aβ1–42-Induced Neuroinflammation and Inhibits NF-κB Pathway

Neuroinflammation induced by beta-amyloid (Aβ) plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and inhibiting Aβ-induced neuroinflammation serves as a potential strategy for the treatment of AD. Oridonin (Ori), a compound of Rabdosia rubescens, has been shown to exert anti-inflammatory effects. In this study, we demonstrated that Ori inhibited glial activation and decreased the release of inflammatory cytokines in the hippocampus of Aβ_1–42-induced AD mice. In addition, Ori inhibited the NF-κB pathway and Aβ_1–42-induced apoptosis. Furthermore, Ori could attenuate memory deficits in Aβ_1–42-induced AD mice. In conclusion, our study demonstrated that Ori inhibited the neuroinflammation and attenuated memory deficits induced by Aβ_1–42, suggesting that Ori might be a promising candidate for AD treatment.     

Intravenous Infusion of Monocytes Isolated from 2-Week-Old Mice Enhances Clearance of Beta-Amyloid Plaques in an Alzheimer Mouse Model

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid (Aβ) senile plaques and tau-associated neurofibrillary tangles. Other disease features include neuroinflammation and cholinergic neurodegeneration, indicating their possible importance in disease propagation. Recent studies have shown that monocytic cells can migrate into the AD brain toward Aβ plaques and reduce plaque burden. The purpose of this study was to evaluate whether the administration of intravenous infusions of ‘young’ CD11b-positive (+) monocytes into an AD mouse model can enhance Aβ plaque clearance and attenuate cognitive deficits. Peripheral monocytes were isolated from two-week-old wildtype mice using the Pluriselect CD11b+ isolation method and characterized by FACS analysis for surface marker expression and effective phagocytosis of 1 μm fluorescent microspheres, FITC-Dextran or FITC-Aβ_1–42. The isolated monocytes were infused via the tail vein into a transgenic AD mouse model, which expresses the Swedish, Dutch/Iowa APP mutations (APPSwDI). The infusions began when animals reached 5 months of age, when little plaque deposition is apparent and were repeated again at 6 and 7 months of age. At 8 months of age, brains were analyzed for Aβ+ plaques, inflammatory processes and microglial (Iba1) activation. Our data show that infusions of two-week-old CD11b+ monocytes into adult APPSwDI mice results in a transient improvement of memory function, a reduction (30%) in Aβ plaque load and significantly in small (<20 μm) and large (>40 μm) plaques. In addition, we observe a reduction in Iba1+ cells, as well as no marked elevations in cytokine levels or other indicators of inflammation. Taken together, our findings indicate that young CD11b+ monocytes may serve as therapeutic candidates for improved Aβ clearance in AD.     

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

One of the neuropathological hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptides (Aβ) in senile plaques. Aβ-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aβ (1–42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNEL-positive cells as well. Thus, we conclude that GA exerts its protective effects against Aβ (1–42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.     

Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms

Alzheimer’s disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ɛ4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates Aβ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on Aβ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2.     

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP^C)-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP^C-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP^C expression in mice with relatively low PrP^C-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP^C-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD.     

Ginsenoside Rg1 Decreases Aβ1–42 Level by Upregulating PPARγ and IDE Expression in the Hippocampus of a Rat Model of Alzheimer's Disease

Background and Purpose

The present study was designed to examine the effects of ginsenoside Rg1 on expression of peroxisome proliferator-activated receptor γ (PPARγ) and insulin-degrading enzyme (IDE) in the hippocampus of rat model of Alzheimer''s disease (AD) to determine how ginsenoside Rg1 (Rg1) decreases Aβ levels in AD.

Experimental Approach

Experimental AD was induced in rats by a bilateral injection of 10 µg soluble beta-amyloid peptide 1–42 (Aβ_1–42) into the CA1 region of the hippocampus, and the rats were treated with Rg1 (10 mg·kg⁻¹, intraperitoneally) for 28 days. The Morris water maze was used to test spatial learning and memory performance. Hematoxylin-eosin staining was performed to analyze the hippocampal histopathological damage. Immunohistochemistry, western blotting, and real-time PCR were used to detect Aβ_1–42, PPARγ, and insulin-degrading enzyme (IDE) expression in the hippocampus.

Key Results

Injection of soluble Aβ_1–42 into the hippocampus led to significant dysfunction of learning and memory, hippocampal histopathological abnormalities and increased Aβ_1–42 levels in the hippocampus. Rg1 treatment significantly improved learning and memory function, attenuated hippocampal histopathological abnormalities, reduced Aβ_1–42 levels and increased PPARγ and IDE expression in the hippocampus; these effects of Rg1 could be effectively inhibited by GW9662, a PPARγ antagonist.

Conclusions and Implications

Given that PPARγ can upregulate IDE expression and IDE can degrade Aβ_1–42, these results indicate that Rg1 can increase IDE expression in the hippocampus by upregulating PPARγ, leading to decreased Aβ levels, attenuated hippocampal histopathological abnormalities and improved learning and memory in a rat model of AD.     

Rescue of Amyloid-Beta-Induced Inhibition of Nicotinic Acetylcholine Receptors by a Peptide Homologous to the Nicotine Binding Domain of the Alpha 7 Subtype

Alzheimer''s disease (AD) is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ) and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs). Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.     

APP Intracellular Domain Impairs Adult Neurogenesis in Transgenic Mice by Inducing Neuroinflammation

Background

A devastating aspect of Alzheimer''s disease (AD) is the progressive deterioration of memory due to neuronal loss. Amyloid precursor protein (APP) occupies a central position in AD and APP-derived amyloid-β (Aβ) peptides are thought to play a pivotal role in disease pathogenesis. Nonetheless, it is becoming clear that AD etiology is highly complex and that factors other than Aβ also contribute to AD pathogenesis. APP intracellular domain (AICD) is generated together with Aβ and we recently showed that AICD transgenic mice recapitulate pathological features of AD such as tau hyperphosphorylation, memory deficits and neurodegeneration without increasing the Aβ levels. Since impaired adult neurogenesis is shown to augment memory deficits in AD mouse models, here we examined the status of adult neurogenesis in AICD transgenic mice.

Methodology/Principal Finding

We previously generated transgenic mice co-expressing 59-residue long AICD fragment and its binding partner Fe65. Hippocampal progenitor cell proliferation was determined by BrdU incorporation at 1.5, 3 and 12 months of age. Only male transgenic and their respective wilt type littermate control mice were used. We find age-dependent decrease in BrdU incorporation and doublecortin-positive cells in the dentate gyrus of AICD transgenic mice suggesting impaired adult neurogenesis. This deficit resulted from decreased proliferation and survival, whereas neuronal differentiation remained unaffected. Importantly, this impairment was independent of Aβ since APP-KO mice expressing AICD also exhibit reduced neurogenesis. The defects in adult neurogenesis are prevented by long-term treatment with the non-steroidal anti-inflammatory agents ibuprofen or naproxen suggesting that neuroinflammation is critically involved in impaired adult neurogenesis in AICD transgenic mice.

Conclusion/Significance

Since adult neurogenesis is crucial for spatial memory, which is particularly vulnerable in AD, these findings suggest that AICD can exacerbate memory defects in AD by impairing adult neurogenesis. Our findings further establish that AICD, in addition to Aβ, contributes to AD pathology and that neuroinflammation plays a much broader role in AD pathogenesis than previously thought.     

Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer’s disease

Regulation of neuroinflammation and β‐amyloid (Aβ) production are critical factors in the pathogenesis of Alzheimer''s disease (AD). Cathepsin E (CatE), an aspartic protease, is widely studied as an inducer of growth arrest and apoptosis in several types of cancer cells. However, the function of CatE in AD is unknown. In this study, we demonstrated that the ablation of CatE in human amyloid precursor protein knock‐in mice, called APP^NL−G−F mice, significantly reduced Aβ accumulation, neuroinflammation, and cognitive impairments. Mechanistically, microglial CatE is involved in the secretion of soluble TNF‐related apoptosis‐inducing ligand, which plays an important role in microglia‐mediated NF‐κB‐dependent neuroinflammation and neuronal Aβ production by beta‐site APP cleaving enzyme 1. Furthermore, cannula‐delivered CatE inhibitors improved memory function and reduced Aβ accumulation and neuroinflammation in AD mice. Our findings reveal that CatE as a modulator of microglial activation and neurodegeneration in AD and suggest CatE as a therapeutic target for AD by targeting neuroinflammation and Aβ pathology.     

Systemic Transplantation of Human Umbilical Cord Derived Mesenchymal Stem Cells-Educated T Regulatory Cells Improved the Impaired Cognition in AβPPswe/PS1dE9 Transgenic Mice

Alzheimer’s disease (AD) is one of most prevalent dementias, which is characterized by the deposition of extracellular amyloid-beta protein (Aβ) and the formation of neurofibrillary tangles within neurons. Although stereotaxic transplantation of mesenchymal stem cells (MSCs) into the hippocampus of AD animal model as immunomodulatory cells has been suggested as a potential therapeutic approach to prevent the progress of AD, it is invasive and difficult for clinical perform. Systemic and central nervous system inflammation play an important role in pathogenesis of AD. T regulatory cells (Tregs) play a crucial role in maintaining systemic immune homeostasis, indicating that transplantation of Tregs could prevent the progress of the inflammation. In this study, we aimed to evaluate whether systemic transplantation of purified autologous Tregs from spleens of AβPPswe/PS1dE9 double-transgenic mice after MSCs from human umbilical cords (UC-MSCs) education in vitro for 3 days could improve the neuropathology and cognition deficits in AβPPswe/PS1dE9 double-transgenic mice. We observed that systemic transplantation of autologous Tregs significantly ameliorate the impaired cognition and reduced the Aβ plaque deposition and the levels of soluble Aβ, accompanied with significantly decreased levels of activated microglia and systemic inflammatory factors. In conclusion, systemic transplantation of autologous Tregs may be an effective and safe intervention to prevent the progress of AD.     

COPS5 Protein Overexpression Increases Amyloid Plaque Burden,Decreases Spinophilin-immunoreactive Puncta,and Exacerbates Learning and Memory Deficits in the Mouse Brain

Brain accumulation of neurotoxic amyloid β (Aβ) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Aβ generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APΔE9 mice (APΔE9/COPS5-Tg) significantly increased Aβ40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for Aβ42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. Aβ40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, Aβ42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased Aβ levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPβ and decreased levels of sAPPα. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo.     

Validation and Characterization of a Novel Peptide That Binds Monomeric and Aggregated β-Amyloid and Inhibits the Formation of Neurotoxic Oligomers

Although the formation of β-amyloid (Aβ) deposits in the brain is a hallmark of Alzheimer disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to Aβ toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble Aβ oligomers is highly desirable for early diagnosis prior to the manifestation of a clinical AD phenotype and also more effective therapies. We have previously reported that a novel 15-amino acid peptide (15-mer), isolated via phage display screening, targeted Aβ and attenuated its neurotoxicity (Taddei, K., Laws, S. M., Verdile, G., Munns, S., D''Costa, K., Harvey, A. R., Martins, I. J., Hill, F., Levy, E., Shaw, J. E., and Martins, R. N. (2010) Neurobiol. Aging 31, 203–214). The aim of the current study was to generate and biochemically characterize analogues of this peptide with improved stability and therapeutic potential. We demonstrated that a stable analogue of the 15-amino acid peptide (15M S.A.) retained the activity and potency of the parent peptide and demonstrated improved proteolytic resistance in vitro (stable to t = 300 min, c.f. t = 30 min for the parent peptide). This candidate reduced the formation of soluble Aβ42 oligomers, with the concurrent generation of non-toxic, insoluble aggregates measuring up to 25–30 nm diameter as determined by atomic force microscopy. The 15M S.A. candidate directly interacted with oligomeric Aβ42, as shown by coimmunoprecipitation and surface plasmon resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar Aβ42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated Aβ42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies.     

BIN1 Is Decreased in Sporadic but Not Familial Alzheimer’s Disease or in Aging

Bridging integrator 1 (BIN1) has been implicated in sporadic Alzheimer’s disease (AD) by a number of genome wide association studies (GWAS) in a variety of populations. Here we measured BIN1 in frontal cortex samples from 24 sporadic AD and 24 age-matched non-dementia brains and correlated the expression of this protein with markers of AD. BIN1 was reduced by 87% (p=0.007) in sporadic AD compared to non-dementia controls, but BIN1 in sporadic AD did not correlate with soluble Aβ (r_s=-0.084, p=0.698), insoluble Aβ (r_s=0.237, p=0.269), Aβ plaque load (r_s=0.063, p=0.771) or phospho-tau load (r_s=-0.160, p=0.489). In contrast to our findings in sporadic AD, BIN1 was unchanged in the hippocampus from 6 cases of familial AD compared to 6 age-matched controls (p=0.488). BIN1 declined with age in a cohort of non-dementia control cases between 25 and 88 years but the correlation was not significant (r_s=-0.449, p=0.081). Although BIN1 is known to have a role in endocytosis, and the processing of the amyloid precursor protein (APP) to form amyloid-β (Aβ) peptides is dependent on endocytosis, knockdown of BIN1 by targeted siRNA or the overexpression of BIN1 in a human neuroblastoma cell line (SH-SY5Y) had no effect on APP processing. These data suggest that the alteration in BIN1 is involved in the pathogenesis of sporadic, but not familial AD and is not a consequence of AD neurodegeneration or the ageing process, a finding in keeping with the numerous GWAS that implicate BIN1 in sporadic AD. However, the mechanism of its contribution remains to be established.     

Apolipoprotein E-Mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

Background

Mutations of the amyloid precursor protein gene (APP) are found in familial forms of Alzheimer''s disease (AD) and some lead to the elevated production of amyloid-β-protein (Aβ). While Aβ has been implicated in the causation of AD, the exact role played by Aβ and its APP precursor are still unclear.

Principal Findings

In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Aβ. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies.

Conclusions

The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE) with neuroprotective activities.     

Memory deficits in APP23/Abca1+/? mice correlate with the level of Aβ oligomers

ABCA1, a member of the ATP-binding cassette family of transporters, lipidates ApoE (apolipoprotein A) and is essential for the generation of HDL (high-density lipoprotein)-like particles in the CNS (central nervous system). Lack of Abca1 increases amyloid deposition in several AD (Alzheimer''s disease) mouse models. We hypothesized that deletion of only one copy of Abca1 in APP23 (where APP is amyloid precursor protein) AD model mice will aggravate memory deficits in these mice. Using the Morris Water Maze, we demonstrate that 2-year-old Abca1 heterozygous APP23 mice (referred to as APP23/het) have impaired learning during acquisition, and impaired memory retention during the probe trial when compared with age-matched wild-type mice (referred to as APP23/wt). As in our previous studies, the levels of ApoE in APP23/het mice were decreased, but the differences in the levels of Aβ and thioflavin-S-positive plaques between both groups were insignificant. Importantly, dot blot analysis demonstrated that APP23/het mice have a significantly higher level of soluble A11-positive Aβ (amyloid β protein) oligomers compared with APP23/wt which correlated negatively with cognitive performance. To confirm this finding, we performed immunohistochemistry with the A11 antibody, which revealed a significant increase of A11-positive oligomer structures in the CA1 region of hippocampi of APP23/het. This characteristic region-specific pattern of A11 staining was age-dependent and was missing in younger APP23 mice lacking Abca1. In contrast, the levels of Aβ*56, as well as other low-molecular-mass Aβ oligomers, were unchanged among the groups. Overall, the results of the present study demonstrate that in aged APP23 mice memory deficits depend on Abca1 and are likely to be mediated by the amount of Aβ oligomers deposited in the hippocampus.     

Curcumin Improves Amyloid β-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway

Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer’s disease (AD). However, the molecular mechanisms underlying curcumin’s effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42), representing a rodent model of Alzheimer’s disease (AD). The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.     

Linking Aβ42-Induced Hyperexcitability to Neurodegeneration,Learning and Motor Deficits,and a Shorter Lifespan in an Alzheimer’s Model

Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly. β-amyloid (Aβ) accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.     

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples

Human apolipoprotein E (apoE) isoforms may differentially modulate amyloid-β (Aβ) levels. Evidence suggests physical interactions between apoE and Aβ are partially responsible for these functional effects. However, the apoE/Aβ complex is not a single static structure; rather, it is defined by detection methods. Thus, literature results are inconsistent and difficult to interpret. An ELISA was developed to measure soluble apoE/Aβ in a single, quantitative method and was used to address the hypothesis that reduced levels of soluble apoE/Aβ and an increase in soluble Aβ, specifically oligomeric Aβ (oAβ), are associated with APOE4 and AD. Previously, soluble Aβ42 and oAβ levels were greater with APOE4 compared with APOE2/APOE3 in hippocampal homogenates from EFAD transgenic mice (expressing five familial AD mutations and human apoE isoforms). In this study, soluble apoE/Aβ levels were lower in E4FAD mice compared with E2FAD and E3FAD mice, thus providing evidence that apoE/Aβ levels isoform-specifically modulate soluble oAβ clearance. Similar results were observed in soluble preparations of human cortical synaptosomes; apoE/Aβ levels were lower in AD patients compared with controls and lower with APOE4 in the AD cohort. In human CSF, apoE/Aβ levels were also lower in AD patients and with APOE4 in the AD cohort. Importantly, although total Aβ42 levels decreased in AD patients compared with controls, oAβ levels increased and were greater with APOE4 in the AD cohort. Overall, apoE isoform-specific formation of soluble apoE/Aβ modulates oAβ levels, suggesting a basis for APOE4-induced AD risk and a mechanistic approach to AD biomarkers.