Rat's trick to escape Alzheimer's disease

Amyloid beta (Abeta) peptides fibril formation and deposition is considered to be the principal pathological hallmark of Alzheimer's disease (AD). However, it remains obscure why AD is precluded by rat/mouse despite the high sequence identity (97%) of rat/mouse Abeta to its human homologue. Based on the recently proposed redox chemistry-based pathogenic model of neurodegenerative diseases, we hypothesize that the lack of key residues of rat/mouse Abeta compared with the human counterpart may account for why rat/mouse is free of AD. At the same time, we propose a new possible redox chemistry-based pathogenic model of AD based on the experimental observations of certain residues in triggering Abeta aggregation. Moreover, it is also interesting to note that non-mammalian Xenopus Abeta contains all the redox chemistry-related key residues and whether it implies that Xenopus Abeta possesses high amyloidogenic potency remains to be determined by further experimental study.     

Conditional inactivation of nicastrin restricts amyloid deposition in an Alzheimer's disease mouse model

Production of Aβ by γ‐secretase is a key event in Alzheimer's disease (AD). The γ‐secretase complex consists of presenilin (PS) 1 or 2, nicastrin (ncstn), Pen‐2, and Aph‐1 and cleaves type I transmembrane proteins, including the amyloid precursor protein (APP). Although ncstn is widely accepted as an essential component of the complex required for γ‐secretase activity, recent in vitro studies have suggested that ncstn is dispensable for APP processing and Aβ production. The focus of this study was to answer this controversy and evaluate the role of ncstn in Aβ generation and the development of the amyloid‐related phenotype in the mouse brain. To eliminate ncstn expression in the mouse brain, we used a ncstn conditional knockout mouse that we mated with an established AD transgenic mouse model (5XFAD) and a neuronal Cre‐expressing transgenic mouse (CamKIIα‐iCre), to generate AD mice (5XFAD/CamKIIα‐iCre/ncstn^f/f mice) where ncstn was conditionally inactivated in the brain. 5XFAD/CamKIIα‐iCre/ncstn^f/f mice at 10 week of age developed a neurodegenerative phenotype with a significant reduction in Aβ production and formation of Aβ aggregates and the absence of amyloid plaques. Inactivation of nctsn resulted in substantial accumulation of APP‐CTFs and altered PS1 expression. These results reveal a key role for ncstn in modulating Aβ production and amyloid plaque formation in vivo and suggest ncstn as a target in AD therapeutics.     

Oxidative stress in Alzheimer's disease: Primary villain or physiological by-product?

Abstract

The prevalence of Alzheimer's disease (AD) is increasing rapidly worldwide due to an ageing population and largely ineffective treatments. In AD cognitive decline is due to progressive neuron loss that begins in the medial temporal lobe and spreads through many brain regions. Despite intense research the pathogenesis of the common sporadic form of AD remains largely unknown. The popular amyloid cascade hypothesis suggests that the accumulation of soluble oligomers of beta amyloid peptides (Aβ) initiates a series of events that cause neuronal loss. Among their putative toxic effects, Aβ oligomers are thought to act as pro-oxidants combining with redox-active metals to produce excessive reactive oxygen and nitrogen species. However, to date the experimental therapies that reduce Aβ load in AD have failed to halt cognitive decline. Another hypothesis proposed by the late Mark Smith and colleagues is that oxidative stress, rather than Aβ, precipitates the pathogenesis of AD. That is, Aβ and microtubule-associated protein tau are upregulated to address the redox imbalance in the AD brain. As the disease progresses, excess Aβ and tau oligomerise to further accelerate the disease process. Here, we discuss redox balance in the human brain and how this balance is affected by ageing. We then discuss where oxidative stress is most likely to act in the disease process and the potential for intervention to reduce its effects.     

Amyloid‐β‐induced occludin down‐regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation

Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer’s disease (AD). A leaky blood–brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid β (Aβ) peptides of 1–40 and 1–42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of Aβ 1–40, the Aβ variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Aβ 1–40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC‐dextran when compared with cells incubated with the scrambled Aβ 1–40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin‐5 and ZO‐1 were unaffected. JNK and p38MAPK inhibition prevented both Aβ 1–40‐mediated down‐regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD.     

DNA cloning and amino acid sequence determination of a major constituent protein of mammalian nucleoli

Using a cDNA probe encoding the nucleolar protein N038 of Xenopus laevis, we have isolated clones that code for the corresponding mammalian protein from cDNA libraries of mouse embryonal carcinoma and fetal liver cells. The murine cDNA-derived amino acid sequence defines a polypeptide of 292 amino acids (including the initial methionine) of a total molecular weight of 32560 and identifies a single 1.5 kb mRNA on Northern blot hybridization. This polypeptide, which is highly homologous to the Xenopus protein N038, displays an organization in three major domains: (1) an aminoterminal portion of 119 amino acids, which shows a striking homology to nucleoplasmin of Xenopus; (2) a central portion of 68 amino acids that contains two extended acidic domains, a shorter of 13 residues and a longer of 29 residues, separated by an interval enriched in positively charged amino acids; (3) a carboxyterminal portion of 105 amino acids, which is almost identical to the reported partial amino acid sequence of human and rat nucleolar protein termed B23. The sequence comparisons show that the murine protein is the mammalian counterpart to the nucleolar protein N038 of Xenopus and is compatible with the idea that both proteins N038 represent the amphibian and murine equivalents to the human and rat nucleolar phosphoprotein B23. Special sequence features and predicted conformations of this protein are discussed in relation to the specific localization and the possible functions of this major nucleolar protein.     

Interactions between amyloid-β and hemoglobin: implications for amyloid plaque formation in Alzheimer's disease

Accumulation of amyloid-β (Aβ) peptides in the brain is one of the central pathogenic events in Alzheimer's disease (AD). However, why and how Aβ aggregates within the brain of AD patients remains elusive. Previously, we demonstrated hemoglobin (Hb) binds to Aβ and co-localizes with the plaque and vascular amyloid deposits in post-mortem AD brains. In this study, we further characterize the interactions between Hb and Aβ in vitro and in vivo and report the following observations: 1) the binding of Hb to Aβ required iron-containing heme; 2) other heme-containing proteins, such as myoglobin and cytochrome C, also bound to Aβ; 3) hemin-induced cytotoxicity was reduced in neuroblastoma cells by low levels of Aβ; 4) Hb was detected in neurons and glial cells of post-mortem AD brains and was up-regulated in aging and APP/PS1 transgenic mice; 5) microinjection of human Hb into the dorsal hippocampi of the APP/PS1 transgenic mice induced the formation of an envelope-like structure composed of Aβ surrounding the Hb droplets. Our results reveal an enhanced endogenous expression of Hb in aging brain cells, probably serving as a compensatory mechanism against hypoxia. In addition, Aβ binds to Hb and other hemoproteins via the iron-containing heme moiety, thereby reducing Hb/heme/iron-induced cytotoxicity. As some of the brain Hb could be derived from the peripheral circulation due to a compromised blood-brain barrier frequently observed in aged and AD brains, our work also suggests the genesis of some plaques may be a consequence of sustained amyloid accretion at sites of vascular injury.     

CHIP modulates APP‐induced autophagy‐dependent pathological symptoms in Drosophila

Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full‐length human APP in Drosophila and established a fly AD model that exhibits multiple AD‐like symptoms. Here we report that depletion of CHIP effectively palliated APP‐induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for APP‐induced autophagy dysfunction, which promotes Aβ production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal APP activity, but also contributes to dysregulated APP metabolism and subsequent AD pathogenesis.     

Evaluation of chronic lead effects in the blood brain barrier system by DCE-CT

BackgroundLead (Pb) is an environmental factor has been suspected of contributing to the dementia including Alzheimer’s disease (AD). Our previous studies have shown that Pb exposure at the subtoxic dose increased brain levels of beta-amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in amyloid precursor protein (APP) transgenic mice, and is hypothesized to inhibit Aβ clearance in the blood- cerebrospinal fluid (CSF) barrier. However, it remains unclear how different levels of Pb affect Aβ clearance in the whole blood-brain barrier system. This study was designed to investigate whether chronic exposure of Pb affected the permeability of the blood-brain barrier system by using the Dynamic Contrast-Enhanced Computerized Tomography (DCE-CT) method.MethodsDEC-CT was used to investigate whether chronic exposure of toxic Pb affected the permeability of the real-time blood brain barrier system.ResultsData showed that Pb exposure increased permeability surface area product, and also significantly induced brain perfusion. However, Pb exposure did not alter extracellular volumes or fractional blood volumes of mouse brain.ConclusionOur data suggest that Pb exposure at subtoxic and toxic levels directly targets the brain vasculature and damages the blood brain barrier system.     

The Recombinant Amyloid-β Peptide Aβ1-42 Aggregates Faster and Is More Neurotoxic than Synthetic Aβ1-42

Aggregation of the amyloid-β (Aβ) peptide is considered a central event in the pathogenesis of Alzheimer's disease (AD). In order to bypass methodological bias related to a variety of impurities commonly present in typical preparations of synthetic Aβ, we developed a simple, generally applicable method for recombinant production of human Aβ and Aβ variants in Escherichia coli that provides milligram quantities of Aβ in very high purity and yield. Amyloid fibril formation in vitro by human Aβ1-42, the key amyloidogenic Aβ species in AD, was completed threefold faster with recombinant Aβ1-42 compared to synthetic preparations. In addition, recombinant Aβ1-42 was significantly more toxic to cultured rat primary cortical neurons, and it was more toxic in vivo, as shown by strongly increased induction of abnormal phosphorylation of tau and tau aggregation into neurofibrillary tangles in brains of P301L tau transgenic mice. We conclude that even small amounts of impurities in synthetic Aβ—including a significant fraction of racemized peptides that cannot be avoided due to the technical limitations of peptide synthesis—prevent or slow Aβ incorporation into the regular quaternary structure of growing β-amyloid fibrils. The results validate the use of recombinant Aβ1-42 for both in vitro and in vivo studies addressing the mechanisms underlying Aβ aggregation and its related biological consequences for the pathophysiology, therapy, and prevention of AD.     

Characterization of the interaction between Aβ 1–42 and glyceraldehyde phosphodehydrogenase

Advances in the understanding of AD pathogenesis have recently provided strong support for a modified Aβ protein cascade hypothesis, stating that several different Aβ assemblies contribute to the triggering of a complex pathological cascade leading to neurodegeneration. Both in vitro and in vivo, Aβ rapidly forms fibrils (fAβ), which are able to interact with various molecular partners, including proteins, lipids and proteoglycans. In a previous study aimed to identify some of these molecular partners of fAβ, we demonstrated that the GAPDH was specifically coprecipitated with fAβ. The aim of this study was to characterize this interaction. First, it was shown by TEM that synthetic GAPDH directly binds fAβ 1–42. Then rat synaptosomal proteins were purified and incubated with different forms of Aβ in various conditions, and the presence of GAPDH among the proteins coprecipitated with Aβ was studied by western blotting. Results showed that the interaction between GAPDH and fAβ 1–42 is nonionic, as is not impaired by increasing salt concentrations. GAPDH is coprecipitated not only by fAβ, but also by nonfibrillar forms of Aβ 1–42. The 41–42 Aβ sequence seems to be important in the interaction of GAPDH and Aβ, as more GAPDH was coprecipitated with fAβ 1–42 than with fAβ 1–40. GAPDH extracted from various subcellular fractions including mitochondria, was shown to interact with fAβ. Our data demonstrate a direct interaction between Aβ and GAPDH and support the possibility that this interaction has an important pathogenic role in AD. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.     

Generation of a novel murine model of Aβ deposition based on the expression of human wild-type amyloid precursor protein gene

Mouse models of Alzheimer disease (AD) have been generated based on Amyloid-β Precursor Protein (AβPP) and the Presenilin (PSEN) gene mutations associated with familial AD (FAD). Such models have provided valuable insights into AD pathogenesis and represent an important research tool for the discovery of potential treatments. To model amyloid deposition in AD, we generated a new mouse line based on the presence of two copies of the genomic region encoding human wild-type AβPP as well as a mutation (L166P) in the murine Psen1. By ~6 months of age, these mice have begun to develop cerebral Aβ pathology with a significant increase in the levels of AβPP C-terminal fragments and Aβ42, as well as increase Aβ42/Aβ40 ratio. Since in the brain and other tissues of these mice, wild-type human AβPP mRNA and protein levels are comparable to those of endogenous AβPP, this model may allow studies about the role of AβPP isoforms in the pathogenesis of AD. This animal model may be suitable to test drugs aimed at inhibiting expression or altering splicing and processing of AβPP, without artifacts associated with the presence of mutations in AβPP or overexpression due to the use of exogenous promoters. These features of the new model are of critical importance in assessing the success of therapeutic interventions.     

Regulation of interleukin‐1β by interferon‐γ is species specific,limited by suppressor of cytokine signalling 1 and influences interleukin‐17 production

Reports describing the effect of interferon‐γ (IFNγ) on interleukin‐1β (IL‐1β) production are conflicting. We resolve this controversy by showing that IFNγ potentiates IL‐1β release from human cells, but transiently inhibits the production of IL‐1β from mouse cells. Release from this inhibition is dependent on suppressor of cytokine signalling 1. IL‐1β and Th17 cells are pathogenic in mouse models for autoimmune disease, which use Mycobacterium tuberculosis (MTB), in which IFNγ and IFNβ are anti‐inflammatory. We observed that these cytokines suppress IL‐1β production in response to MTB, resulting in a reduced number of IL‐17‐producing cells. In human cells, IFNγ increased IL‐1β production, and this might explain why IFNγ is detrimental for multiple sclerosis. In mice, IFNγ decreased IL‐1β and subsequently IL‐17, indicating that the adaptive immune response can provide a systemic, but transient, signal to limit inflammation.     

RTN4B‐mediated suppression of Sirtuin 2 activity ameliorates β‐amyloid pathology and cognitive impairment in Alzheimer's disease mouse model

Sirtuin 2 (SIRT2) is an NAD+ dependent deacetylase that is the most abundant sirtuin protein in the brain. Accumulating evidence revealed the role of SIRT2 in a wide range of biological processes and age‐related diseases. However, the pivotal mechanism of SIRT2 played in Alzheimer's disease (AD) remains unknown. Here, we report that pharmacological inactivation of SIRT2 has a beneficial effect in AD. The deacetylase inhibitor of SIRT2 rescued the cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mouse (APP/PS1 mouse), and the BACE1 cleavage was weakened to reduce the β‐amyloid (Aβ) production in the hippocampus. Moreover, we firstly identified that Reticulon 4B (RTN4B) played a crucial role between SIRT2/BACE1 regulation in AD. RTN4B, as a deacetylation substrate for SIRT2, the deacetylation by SIRT2 drived the ubiquitination and degradation of RTN4B and then the disturbed RTN4B interacted with and influenced the expression of BACE1. When we overexpressed RTN4B in neurons of the hippocampus in the AD mouse model, the abnormal Aβ accumulation and cognitive impairment were ameliorated, consistent with the results of SIRT2 inhibition in vivo. Moreover, we showed that the regulatory effect of SIRT2 on BACE1 is dependent on RTN4B. When RTN4B was knocked down, the effects of SIRT2 inhibition on the BACE1 level, Aβ pathology, and AD‐liked behaviors were also blocked. Collectively, we provide evidence that SIRT2 may be a potential target for AD; the new found SIRT2/RTN4B/BACE1 pathological pathway is one of the critical mechanisms for the improvement of SIRT2 on AD.     

Key roles of Arg,Tyr and His residues in Aβ–heme peroxidase: Relevance to Alzheimer’s disease

Recent reports show that heme binds to amyloid β-peptide (Aβ) in the brain of Alzheimer’s disease (AD) patients and forms Aβ–heme complexes, thus leading a pathological feature of AD. However, the important biological relevance to AD etiology, resulting from human Aβ–heme peroxidase formation, was not well characterized. In this study, we used wild-type and mutated human Aβ_1–16 peptides and investigated their Aβ–heme peroxidase activities. Our results indicated that both histidine residues (His¹³, His¹⁴) in Aβ_1–16 and free histidine enhanced the peroxidase activity of heme, hence His residues were essential in peroxidase activity of Aβ–heme complexes. Moreover, Arg⁵ was found to be the key residue in making the Aβ_1–16–heme complex as a peroxidase. Under oxidative and nitrative stress conditions, the Aβ_1–16–heme complexes caused oxidation and nitration of the Aβ Tyr¹⁰ residue through promoting peroxidase-like reactions. Therefore, these residues (Arg⁵, Tyr¹⁰ and His) were pivotal in human Aβ–heme peroxidase activity. However, three of these residues (Arg⁵, Tyr¹⁰ and His¹³) identified in this study are all absent in rodents, where rodent Aβ–heme complex lacks peroxidase activity and it does not show AD, implicating the novel significance of these residues as well as human Aβ–heme peroxidase in the pathology of AD.     

Gardenia jasminoides J.Ellis extract GJ-4 alleviated cognitive deficits of APP/PS1 transgenic mice

BackgroundAccumulating evidence demonstrates that traditional Chinese medicines that act on multiple targets could effectively treat various multi-etiological diseases, including cerebrovascular diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and so on. Previous studies have shown that crocin richments (GJ-4), Gardenia jasminoides J.Ellis extract, provide neuroprotective effects on cognitive impairments in AD mouse models. However, the mechanism how GJ-4 improves cognition remains still unclear.PurposeThe aim of this study was to uncover the protective effects and underlying mechanism of GJ-4 on PrP-hAβPPswe/PS1^ΔE9 (APP/PS1) transgenic mice.MethodsAPP/PS1 mice were given GJ-4 (10, 20, and 50 mg/kg), donepezil (5 mg/kg) and memantine (5 mg/kg) orally at eight months of age for 12 consecutive weeks. Morris water maze and novel object recognition were conducted to assess the cognitive ability of mice. The release of inflammatory cytokines was determined by RT-PCR assay, and the pathological features of neurons and microglia were assayed by immunohistochemistry and immunofluorescence assay. The expression of Aβ-related proteins and signaling pathways were determined by Western blot.ResultsThe behavioral results revealed that GJ-4 ameliorated the cognitive deficits of APP/PS1 mice measured by Morris water maze and novel object recognition tests. Mechanism studies indicated that GJ-4 significantly decreased β-amyloid (Aβ) level through reducing Aβ production and promoting Aβ degradation. It has been reported that Aβ plaques trigger the hyper-phosphorylation of tau protein in APP/PS1 mice. Consistent with previous studies, hyper-phosphorylation of tau was also occurred in APP/PS1 mice in the present study, and GJ-4 inhibited Tau phosphorylation at different sites. Overwhelming evidence indicates that neuroinflammation stimulated by Aβ and hyperphosphorylated tau is involved in the pathological progression of AD. We found that GJ-4 suppressed neuroinflammatory responses in the brain through regulating phosphatidylinositide 3-kinase/AKT (PI3K/AKT) signaling pathway activation, and subsequent expression of inflammatory proteins and release of inflammatory cytokines.ConclusionAltogether, GJ-4 ameliorated cognition of APP/PS1 transgenic mice through multiple targets, including Aβ, tau and neuroinflammation. This study provides a solid research basis for further development of GJ-4 as a potential candidate for the treatment of AD.     

Prostaglandin I2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

Cyclooxygenase‐2 (COX‐2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX‐2 metabolic product, prostaglandin (PG) I₂, in the pathogenesis of AD remains unknown. Using human‐ and mouse‐derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx‐defective (APH)‐1α and pharynx‐defective‐1β induction. In particular, we found that PGI₂ production increased during the course of AD development. Then, PGI₂ accumulation in neuronal cells activates PKA/CREB and JNK/c‐Jun signaling pathways by phosphorylation, which results in APH‐1α/1β expression. As PGI₂ is an important metabolic by‐product of COX‐2, its suppression by NS398 treatment decreases the expression of APH‐1α/1β in neuronal cells and APP/PS1 mice. More importantly, β‐amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH‐1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH‐1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI₂‐induced AD progression but also are instrumental for improving clinical therapies to combat AD.     

Binding between Prion Protein and Aβ Oligomers Contributes to the Pathogenesis of Alzheimer's Disease

A plethora of evidence suggests that protein misfolding and aggregation are underlying mechanisms of various neurodegenerative diseases, such as prion diseases and Alzheimer's disease(AD). Like prion diseases, AD has been considered as an infectious disease in the past decades as it shows strain specificity and transmission potential. Although it remains elusive how protein aggregation leads to AD, it is becoming clear that cellular prion protein(PrP~C ) plays an important role in AD pathogenesis. Here, we briefly reviewed AD pathogenesis and focused on recent progresses how PrP~C contributed to AD development. In addition, we proposed a potential mechanism to explain why infectious agents, such as viruses, conduce AD pathogenesis. Microbe infections cause Aβ deposition and upregulation of PrP~C , which lead to high affinity binding between Aβ oligomers and PrP~C . The interaction between PrP~C and Aβ oligomers in turn activates the Fyn signaling cascade, resulting in neuron death in the central nervous system(CNS). Thus, silencing PrP~C expression may turn out be an effective treatment for PrP~C dependent AD.     

APP mouse models for Alzheimer's disease preclinical studies

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.     

Amyloid β serves as an NGF‐like neurotrophic factor or acts as a NGF antagonist depending on its concentration

In the nervous system, both the shape and connectivity of neurons are strongly influenced by soluble, extracellular factors. Indeed, we recently demonstrated that after binding to p75^NTR, the common neurotrophin receptor, nerve growth factor (NGF) controls the morphology and connectivity of cultured mouse hippocampal neurons by encouraging the production of fewer yet longer dendrites, and by augmenting GABAergic connectivity. These effects of NGF are mediated by the differential expression of Enhancer‐of‐split 1/5 homologs and neurogenin 3. Amyloid β (Aβ), a pathogenic agent in Alzheimer’s disease (AD) is known to bind to p75^NTR, hence we studied its influence on cultured hippocampal neurons. At 800 nM, Aβ(1–40) prevents NGF‐induced activation of NF‐κB and consequently, it depresses the expression of Enhancer‐of‐split 1. Thus, at this concentration, the effect of Aβ on neurons is antagonistic to those provoked by NGF and accordingly, neurons sprout more yet shorter dendrites and their GABAergic input decreases. In contrast, at lower concentration, 20 nM, the amyloid induces cellular effects similar to those induced by NGF, both in terms of gene expression, neuronal morphology, and GABAergic connectivity. Our results demonstrate that Aβ may act as a neurotrophic factor that mimics the activity of NGF. However, at higher concentrations, the amyloid behaves as an antagonist of NGF, contributing to the advent of AD.