Pentosidine determination in CSF: a potential biomarker of Alzheimer's disease?

BACKGROUND: The histopathological hallmarks in Alzheimer's disease (AD) include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. Glycoxidation plays a crucial role in AD pathogenesis, as pentosidine and Nε- carboxymethyl-lysine (CML), were detected in AD hallmarks, and in vivo cerebrospinal fluid (CSF). However, the definitive role of AGEs in the neuropathology of AD is inconclusive. The aim of this preliminary study was to assess the level of pentosidine in CSF of patients affected by neurological disorders, including probable AD, in order to assess the feasibility of AGEs detection in CSF and to explore pentosidine as a potential biomarker in AD. METHODS: Twenty-five patients diagnosed with AD (NINCDS ADRDA criteria) and different neurological disorders were enrolled. Diabetic patients were excluded. Pentosidine, CML, amyloid ß1-42 were assessed by high performance liquid chromatography (HPLC) by Odetti modified method,and by sandwich ELISA respectively. RESULTS: Our data showed the presence of pentosidine in all CSF samples, a significant increase in CSF pentosidine levels with age (p<0.05) and a significant decreased concentration of pentosidine in four AD subjects (p<0.01), after normalization to CSF protein concentration. CONCLUSIONS: The study showed that AGEs concentration in CSF might benefit from age correction, at least for pentosidine, originally addressing a potential systemic age-dependent AGEs accumulation. The significant decrease of CSF pentosidine in AD, even in 4 patients, might conceive that different AGEs inform specific types of neurodegeneration, depending on oxidative stress levels, blood - brain barrier permeability, brain localization and systemic risk factors.

Structural alterations of human serum albumin caused by glycative and oxidative stressors revealed by circular dichroism analysis.

The aim of this work was to evaluate the ability of oxidative and glycative stressors to modify properties of human serum albumin (HSA) by analyzing markers of glycation (pentosidine) and oxidation (advanced oxidative protein products (AOPPs)) and assessing fluorescence and circular dichroism. HSA was incubated for up to 21 days with ribose, ascorbic acid (AA) and diethylenetriamine pentacetate (DTPA) in various combinations in order to evaluate influences of these substances on the structure of HSA. Ribose was included as a strong glycative molecule, AA as a modulator of oxidative stress, and DTPA as an inhibitor of metal-catalyzed oxidation. Ribose induced a significant increase in pentosidine levels. AA and DTPA prevented the accumulation of pentosidine, especially at later time points. Ribose induced a mild increase in AOPP formation, while AA was a strong inducer of AOPP formation. Ribose, in combination with AA, further increased the formation of AOPP. DTPA prevented the AA-induced generation of AOPP. Ribose was also a potent inducer of fluorescence at 335nm ex/385nm em, which is typical of pentosidine. AA and DTPA prevented this fluorescence. Circular dichroism showed complex results, in which AA and DTPA were strong modifiers of the percentages of the alpha-helical structure of HSA, while ribose affected the structure of HSA only at later time points.

ß-amyloid 1-42 induces physiological transcriptional regulation of BACE1.

The pathogenesis of Alzheimer's disease (AD) is only partially understood. ß-amyloid (Aß) is physiologically generated by sequential cleavage of its precursor protein by the ß- and the γ-secretase and it is normally disposed of. In Alzheimer's disease, Aß is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the ß-secretase cleavages of Aß precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aß precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of ß-secretase which is induced by Presenilin 1 mutations. Then, Aß 1-42 is the Aß precursor protein derivative that up-regulates the expression of ß-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of ß-secretase and c-jun N-terminal kinase related proteins by monomeric Aß 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric Aß 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of ß-secretase.

Dysregulation of SREBP2 induces BACE1 expression.

ß-Amyloid hyperproduction has been observed in response to alterations in neuronal intracellular cholesterol storage, efflux, and synthesis, induced in rats by a high-fat diet. It has been suggested that cholesterol homeostasis is altered in Alzheimer's disease resulting in higher ß- and γ-secretase activity. In the current study the neuronal activation status of sterol regulatory element binding protein 2 (SREBP2) as well as its involvement in ß-secretase BACE1 activity was investigated in high-fat fed rats (26% fat and 4% cholesterol for 20 weeks), and in SK-N-BE neuroblastoma cells exposed to 20 µM cholesterol. This work demonstrates that in the brain a hyperlipidic diet is able to induce a hyper-expression of BACE1 and determine an unbalance in cerebral cholesterol homeostasis so that SREBP2 is activated. In addition, we show for the first time the involvement of SREBP2 on expression of BACE1 in SK-N-BE cells exposed to high cholesterol. Although the enhanced risk of Alzheimer's disease in metabolic syndrome is related to several factors, our results suggest that SREBP2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer's disease progression.

17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease.

Alternative splicing is a central component of human brain complexity; nonetheless, its regulatory mechanisms are still largely unclear. In this work, we describe a novel non-coding (nc) RNA (named 17A) RNA polymerase (pol) III-dependent embedded in the human G-protein-coupled receptor 51 gene (GPR51, GABA B2 receptor). The stable expression of 17A in SHSY5Y neuroblastoma cells induces the synthesis of an alternative splicing isoform that abolish GABA B2 intracellular signaling (i.e., inhibition of cAMP accumulation and activation of K(+) channels). Indeed, 17A is expressed in human brain, and we report that it is upregulated in cerebral tissues derived from Alzheimer disease patients. We demonstrate that 17A expression in neuroblastoma cells enhances the secretion of amyloid ß peptide (Aß) and the Aß x-42/Αß x-40 peptide ratio and that its synthesis is induced in response to inflammatory stimuli. These data correlate, for the first time, the activity of a novel pol III-dependent ncRNA to alternative splicing events and, possibly, to neurodegeneration induced by abnormal GABA B function. We anticipate that further analysis of pol III-dependent regulation of alternative splicing will disclose novel regulatory pathways associated to brain physiology and/or pathology.

Investigation of hallmarks of carbonyl stress and formation of end products in feline chronic kidney disease as markers of uraemic toxins.

OBJECTIVES: Cats are commonly affected by chronic kidney disease (CKD). Many reactive carbonyl intermediates and end products originating from the oxidative stress pathways are recognised as uraemic toxins and may play a role in CKD progression. The aim of the present study is to confirm whether carbonyl end-product formation is higher in cats affected by CKD and to assess whether an angiotensin-converting enzyme inhibitor (ACEi) might affect these hallmarks. METHODS: Twenty-two cats were divided into three groups: a control group (CG), cats with CKD and cats with CKD treated with an ACEi. Serum levels of pentosidine, carboxymethyllysine, advanced oxidation protein products, malondialdehyde, methylglyoxal and hexanoyl-lysine were measured. In addition, biochemical parameters and systolic blood pressure were evaluated. After checking for normality, comparisons between groups were performed followed by multiple comparison tests. P values ⩽0.05 were considered significant. Correlations between concentrations of the considered biomarkers and of the other metabolic parameters were investigated. RESULTS: Advanced oxidation protein products, malondialdehyde and hexanoyl-lysine concentrations were significantly higher in CKD and ACEi-treated groups compared with the CG ( P <0.05). Carboxymethyllysine increased in the ACEi-treated group when compared with the CG, whereas intermediate values of these biomarkers were found in the CKD group ( P <0.05). The ACEi-treated group showed the highest values of carboxymethyllysine, advanced oxidation protein products and hexanoyl-lysine. By contrast, the CKD group had the highest concentration of malondialdehyde. No statistically significant difference was found in the levels of pentosidine or methylglyoxal. End products correlated with creatinine and urea and with each other. CONCLUSIONS AND RELEVANCE: Significantly high concentrations of both intermediate and end products of carbonyl/oxidative stress were detected in CKD cats. This is the first study to have concurrently taken into account several uraemic toxins and biochemical parameters in cats affected by CKD.

Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein.

Sequential cleavages of the beta-amyloid precursor protein cleaving enzyme 1 (BACE1) by beta-secretase and gamma-secretase generate the amyloid beta-peptides, believed to be responsible of synaptic dysfunction and neuronal cell death in Alzheimer's disease (AD). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying mechanism is unknown. Here we show that oxidative stress (OS) stimulates BACE1 expression by a mechanism requiring gamma-secretase activity involving the c-jun N-terminal kinase (JNK)/c-jun pathway. BACE1 levels are increased in response to OS in normal cells, but not in cells lacking presenilins or amyloid precursor protein. Moreover, BACE1 is induced in association with OS in the brains of mice subjected to cerebral ischaemia/reperfusion. The OS-induced BACE1 expression correlates with an activation of JNK and c-jun, but is absent in cultured cells or mice lacking JNK. Our findings suggest a mechanism by which OS induces BACE1 transcription, thereby promoting production of pathological levels of amyloid beta in AD.

Pectin-honey hydrogel: Characterization, antimicrobial activity and biocompatibility.

BACKGROUND: Novel pectin-honey hydrogels have been developed and characterized as medical device. Ideally, a wound dressing should maintain optimal fluid affinity, permit moisture evaporation, protect the wound from microbes, and have shape-conformability, biocompatibility, and antibacterial activity. OBJECTIVE: A novel, simple and fast method to produce pectin-honey wound dressings is described. METHODS: The properties of these pectin-honey hydrogels were investigated, including swelling ability, water vapour transmission rate, hydrogen peroxide production, methylglyoxal content and antibacterial activity. Biocompatibility was assessed by proliferation assays using cultured fibroblast cells and by in vivo study with subcutaneous and intraperitoneal implantation in rats. RESULTS: Hydrogel showed a good water vapour transmission rate, fluid uptake and were not cytotoxic for fibroblasts. The hydrogel demonstrated good antibacterial activity toward clinically relevant pathogens, including S. aureus and E. coli. Biocompatibility was confirmed by the measurement of plasma levels of interleukin (IL)1 beta, IL-6, tumour necrosis factor (TNF) alpha, and prostaglandin (PG)E2. No histological changes were observed. CONCLUSIONS: The presence of a natural active component, conformability, and complete resorbability are the main characteristics of this new biocompatible biomaterial that is well tolerated by the body, possibly improves healing, may be used for surgical complications prevention, with a simple and inexpensive production process.

Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype.

OBJECTIVE: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. DESIGN: Description of a novel phenotype associated with a presenilin 1 mutation. SETTING: The subject was an outpatient who was diagnosed at the local referral center. PATIENT: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe beta-amyloid (Abeta) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. MAIN OUTCOME MEASURES: We analyzed the processing of Abeta precursor protein in vitro as well as the Abeta species in brain tissue. RESULTS: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Abeta(42) and Abeta(40) species and a 60% increase of secreted Abeta precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Abeta species ending at both residues 40 and 42. CONCLUSION: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Abeta aggregates' composition.

Vitamin C, Aging and Alzheimer's Disease.

Accumulating evidence in mice models of accelerated senescence indicates a rescuing role of ascorbic acid in premature aging. Supplementation of ascorbic acid appeared to halt cell growth, oxidative stress, telomere attrition, disorganization of chromatin, and excessive secretion of inflammatory factors, and extend lifespan. Interestingly, ascorbic acid (AA) was also found to positively modulate inflamm-aging and immunosenescence, two hallmarks of biological aging. Moreover, ascorbic acid has been shown to epigenetically regulate genome integrity and stability, indicating a key role of targeted nutrition in healthy aging. Growing in vivo evidence supports the role of ascorbic acid in ameliorating factors linked to Alzheimer's disease (AD) pathogenesis, although evidence in humans yielded equivocal results. The neuroprotective role of ascorbic acid not only relies on the general free radical trapping, but also on the suppression of pro-inflammatory genes, mitigating neuroinflammation, on the chelation of iron, copper, and zinc, and on the suppression of amyloid-beta peptide (Aß) fibrillogenesis. Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease is rapidly increasing. Thus, dietary interventions, as a way to epigenetically modulate the human genome, may play a role in the prevention of AD. The present review is aimed at providing an up to date overview of the main biological mechanisms that are associated with ascorbic acid supplementation/bioavailability in the process of aging and Alzheimer's disease. In addition, we will address new fields of research and future directions.

Do Cancer Drugs Counteract Neurodegeneration? Repurposing for Alzheimer's Disease.

In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer's disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD.

Evaluation of prognostic indices in elderly hospitalized patients.

AIM: Prognosis informs the physician's decision-making process, especially for frail older adults. So far, any non-disease-specific index has proven full evidence for routine use in clinical practice. Here, we aimed at assessing, prospectively, the calibration and discriminating accuracy of validated prognostic indices in a cohort of elderly hospitalized patients. METHODS: This was a prospective observational study that enrolled elderly patients (n = 100). The patients' assessment included clinical variables, as well as the following five prognostic indices of mortality: (i) Levine index (2007); (ii) Walter index (2001); (iii) CARING (C, primary diagnosis of cancer; A, ≥ 2 admissions to the hospital for a chronic illness within the last year; R, resident in a nursing home; I, intensive care unit admission with multiorgan failure, NG, noncancer hospice guidelines [meeting ≥ 2 of the National Hospice and Palliative Care Organization's guidelines]) criteria of Fischer (2006-2011); (iv) Silver Code of Di Bari (2010); and (v) Burden of Illness Score for Elderly Persons of Inouye (2003). RESULTS: Patients' clinical characteristics: 70% women (age 86.20 ± 0.69 years), 30% men (age 85.40 ± 1.07 years), Comorbidity Illness rating scale (CIRS) 4.3 ± 0.61 and Barthel Index 28 ± 0.54. Walter and Burden of Illness Score for Elderly Persons scores showed similar prediction rates when compared with the expected validated values (ancova: F = 14.00, P < 0.008). Burden of Illness Score for Elderly Persons was the most calibrated and accurate index (receiver operating characteristic curve 0.72; P < 0.02). CONCLUSIONS: None of the assessed prognostic indices, in a "real world" scenario, afforded the optimal predictive accuracy (receiver operating characteristic curve 0.90); all these indices are still far from a robust answer to the prognosis in older age, reflecting a poor ability to encompass the spectrum of frailty. Effort should be made to tailor the prognostication in geriatrics, moving from a disease-centered model to a precision model, tailored to the frail phenotype. Geriatr Gerontol Int 2017; 17: 1015-1021.

Beta-amyloid 1-42 monomers, but not oligomers, produce PHF-like conformation of Tau protein.

The mechanistic relationship between amyloid ß1-42 (Aß1-42) and the alteration of Tau protein are debated. We investigated the effect of Aß1-42 monomers and oligomers on Tau, using mice expressing wild-type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aß1-42, mice were sacrificed after 3 h or 4 days. The short-lasting treatment with Aß monomers, but not oligomers, showed a conformational PHF-like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aß monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aß oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aß1-42 monomers foster synaptic activity. Our results suggest that Aß monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti-Aß therapies should be targeted to Aß1-42 monomers too.

Neprylisin decreases uniformly in Alzheimer's disease and in normal aging.

The proteolysis of beta-amyloid (Abeta) requires neprylisin, an enzyme that has been shown as reduced in Alzheimer's disease (AD). We investigated whether a decrease in neprilysin levels contributes to the accumulation of amyloid deposits not only in AD but also in the normal aging. We analyzed neprilysin mRNA and protein levels in cerebral cortex from 10 cognitively normal elderly subjects with amyloid plaques (NA), 10 cases of AD, and 10 control cases free of amyloid plaques. We found a significant decrease in neprilysin mRNA levels in both AD and NA compared to control cases. Thereby, the defect of neprilysin appears to correlate with Abeta deposition but not with degeneration and dementia.

Plasma levels of insulin and amyloid beta 42 are correlated in patients with amnestic Mild Cognitive Impairment.

Epidemiological and experimental data suggest that type 2 diabetes (DM2) and sporadic late-onset Alzheimer's disease (AD) share a common mechanism, that is able to produce accumulation of insulin and amyloid beta 42 (Abeta42), the major pathogenic events respectively of the two conditions. In 71 non diabetic patients with amnestic mild cognitive impairment we found a significant linear correlation between fasting plasma levels of insulin and Abeta42 (R = +0.25, P < 0.05). The levels of both peptides were elevated in comparison to 48 age-matched cognitively normal controls. The correlation of insulin and Abeta42 plasma levels suggests a pathogenic link between DM2 and sporadic AD.

Amnestic mild cognitive impairment and conversion to Alzheimer's disease: insulin resistance and glycoxidation as early biomarker clusters.

Autopsy studies have indicated brain accumulation of amyloid-ß peptides as a common pathogenetic hallmark of amnestic cognitive impairment (aMCI) and overt Alzheimer's disease (AD). The pathogenesis of AD is still debated but recent reports have even designated AD as type III diabetes. This study aims to assess plasma levels of malondialdehyde, pentosidine, and insulin resistance in a group of aMCI patients, AD subjects, and age- and gender-matched controls, to confirm, beyond the accumulation of amyloid-ß, the presence of a metabolic disorder, as a causative/contributive factor for AD. Patients were recruited and diagnosed as aMCI (n = 180), AD (n = 84), and age- and gender-matched controls (n = 62) at three different Italian memory clinics. Plasma insulin and glucose, plasma pentosidine and malondialdehyde (MDA), HOMA-IR and QUICKI score for insulin sensitivities indexes were collected at the basal visit. Plasma MDA levels were higher in the aMCI group who converted to AD compared to controls, stable aMCI subjects, and AD subjects (p < 0.01) respectively, while plasma pentosidine was higher compared to controls. The aMCI group showed a significant correlation between HOMA-IR, QUICKI, insulin, and MDA (p < 0.02). aMCI might be considered the early biochemical active disease stage where glycoxidation, hyperinsulinemia, and pro-amyloidogenic status are at the highest rate while overt AD might indicate the glycoxidative cascade dwindling, ending a process possibly started two decades earlier.

Soluble amyloid beta-protein is increased in frontotemporal dementia with tau gene mutations.

The relationship between senile plaques and neurofibrillary tangles, the main pathologic lesions of Alzheimer's disease, is not completely understood. We addressed this issue examining the type and amount of amyloid beta-protein (Abeta) associated with the soluble and insoluble tissue fractions in the frontal cortex of 8 cases with frontotemporal dementia with parkinsonism caused by mutations of the Tau gene (FTDP-17), in which the intracellular accumulation of polymerised tau is definitely the primary cause of neurodegeneration. As control, we examined 7 cases with frontotemporal dementia lacking distinctive histopathology (DLDH) as well as 8 pathologically normal subjects. In all cases the presence of Abeta deposits was ruled out using immunocytochemistry on sections adjacent to those used for biochemical analysis. ELISA analysis showed a 2.7 and 2.1 fold (p < 0.01) increase of soluble Abeta42 and Abeta40 in FTDP-17, compared to normal and DLDH brains, both of which had comparable levels of Abeta species. Furthermore, the immunoreactivity of the intracellular Abeta42 was significantly increased in cortical neurons of subjects affected with FTDP-17. The results demonstrate that the aggregation of tau protein produces an accumulation of Abeta, which, however, does not reach the critical concentration needed for Abetaplaques formation.

Neuronal apoptosis is accompanied by amyloid beta-protein accumulation in the endoplasmic reticulum.

A series of evidences suggests that enhanced susceptibility to programmed cell death (PCD) is a major pathogenetic factor in Alzheimer's disease (AD). We investigated this issue, analyzing amyloid beta-protein (A beta) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280-290% secreted A beta occurred, in spite of a 20% metabolism and an unchanged A betaPP expression. The increased intracellular A beta reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus of beta PP, but only partially rescued A beta overproduction caused by staurosporine treatment. Our findings suggest that PCD fosters the physiological pathways of A beta production characteristic of neuronal cells, and they confirm the theory that unbalance of PCD is a central event in AD pathogenesis. Moreover, our data indicate that still unidentified cellular mechanisms, other than caspases activation, are responsible of the specific alteration of A betaPP processing during PCD.

Protein levels of glycogen synthase 3 kinase are normal in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by pure neurofibrillary tau pathology involving mainly basal ganglia and brain stem nuclei. One of the kinases involved in tau phosphorylation is glycogen synthase 3 kinase (GSK3). In mammals GSK3 is present in two isoforms, alpha and beta regulated by phosphorylation: phosphorylation of Ser9 in GSK3beta or Ser21 in GSK3alpha leads to inactivation while phosphorylation of Tyr216 in GSK3beta or Tyr279 in GSK3alpha leads to activation. We analyzed the protein levels of GSK3alpha/beta and of the phosphorylated forms GSK3beta S(9), GSK3beta Y(216), GSK3alpha Y(279) in brain tissues of subjects with PSP. The analysis failed to show significant differences of all GSK3 isoforms in PSP in comparison to age-matched control cases. This negative result argues against the role of GSK3 in the pathogenesis of PSP.

Monomeric Aß1-42 and RAGE: key players in neuronal differentiation.

The aggregation of amyloid-ß (Aß) peptides plays a crucial role in the onset and progression of Alzheimer's disease. Monomeric form of Aß, indeed, could exert a physiological role. Considering the anti-oligomerization property of all-trans retinoic acid (ATRA), the involvement of monomeric Aß1-42 in ATRA-induced neuronal differentiation has been investigated. Four-day ATRA treatment increases ß-secretase 1 (BACE1) level, Aß1-42 production, and receptor for advanced glycation end-products (RAGE) expression. RAGE is a well-recognized receptor for Aß, and the block of both RAGE and Aß1-42 with specific antibodies strongly impairs neurite formation in ATRA-treated cells. The involvement of Aß1-42 and RAGE in ATRA-induced morphologic changes has been confirmed treating undifferentiated cells with different molecular assemblies of peptide: 1 µM monomeric, but not oligomeric, Aß1-42 increases RAGE expression and favors neurite elongation. The block of RAGE completely prevents this effect. Furthermore, our data underline the involvement of the RAGE-dependent adhesion molecule amphoterin-induced gene and open reading frame-1 as downstream effector of both ATRA and Aß1-42. In conclusion, our findings identify a novel physiological role for monomeric Aß1-42 and RAGE in neuronal differentiation.