Search results for "amyloid beta"

LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier.

2011

According to the "amyloid hypothesis", the amyloid-β (Aβ) peptide is the toxic intermediate driving Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that the low density lipoprotein receptor-related protein 1 (LRP1) transcytoses Aβ out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of Aβ across the BBB we analyzed Aβ transcytosis across primary mouse brain capillary endothelial cells (pMBCECs) derived from wild-type and LRP1 knock-in mice. Here, we show that pMBCECs in vitro express functionally active LRP1. Moreover, we demonstrate that LRP1 mediates transcytosis of [(125)I]-Aβ(1-40) across pMBCECs in both direct…

β-Amyloid-induced activation of Caspase-3 in primary cultures of rat neurons

2000

It is known that beta-amyloid peptide (Abeta) contributes to the neurodegeneration in Alzheimer's disease (AD) and operates through activation of an apoptotic pathway. Apoptotic signal is driven by a family of cysteine proteases called caspases. The beta-amyloid precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated beta-amyloid peptide formation. Cerebellar neurons from rat pups were treated with the aged Abeta(25-35) at 1 and 5 microM and fluorescence assays of caspase activity performed over 4 days. We observed an increase in caspase activity after 48 h treatment in both 1 and 5 microM treated cells, then (72-96 h) caspase activity…

Pharmacological intervention in age-associated brain disorders by Flupirtine: Alzheimer’s and Prion diseases

1998

Alzheimer's disease, a major form of dementia in the elderly has become an increasingly important health problem in developed countries. In vitro studies on primary neurons demonstrate that Flupirtine (Katadolon) at a concentration of 1 microg/ml, significantly reduces the neurotoxic (apoptotic) effect displayed by A beta25-35, a segment of the amyloid beta-protein precursor the etiologic agent of Alzheimer's disease. Flupirtine, which has been in clinical use since 10 years ago, prevents the toxic effect of PrP, the presumed etiologic agent of the Creutzfeldt-Jakob disease as well as the excitatory amino acid glutamate on cortical neurons. Flupirtine displays a bimodal activity. Its strong…

Insulin-activated Akt rescues Aβ oxidative stress-induced cell death by orchestrating molecular trafficking

2011

Increasing evidence indicates that Alzheimer's disease, one of the most diffused aging pathologies, and diabetes may be related. Here, we demonstrate that insulin signalling protects LAN5 cells by amyloid-β42 (Aβ)-induced toxicity. Aβ affects both activation of insulin receptors and the levels of phospho-Akt, a critical signalling molecule in this pathway. In contrast, oxidative stress induced by Aβ can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro-apoptotic transcription factor activated by reactive oxygen species generation. Insulin cascade protects against mitochondrial damage caused by Aβ treatment, restoring the mitochondrial membrane potential. Moreover, we show t…

Antioxidants as a Potential Therapy Against Age-Related Neurodegenerative Diseases: Amyloid Beta Toxicity and Alzheimers Disease

2006

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder with distinct neuropathological features. Extracellular plaques, consisting of aggregated amyloid peptides of 39-43 amino acids are one of the most prominent pathological hallmarks of this disease. Although the exact neurochemical effector mechanism of Abeta aggregation is not yet elucidated, age-associated disturbances of metal ion metabolism have been proposed to promote the formation of aggregates from soluble Abeta. Oxidative stress is postulated to be a downstream effect of Abeta-metal ion interactions. Therefore, the modulation of brain metal metabolism and attenuation of oxidative stress by antioxidant m…

Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid de…

2012

Alzheimer's disease (AD) is characterized by amyloid-beta deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1(-/-) mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its …

CHARACTERIZATION OF THE SYNAPTIC PROTEOME IN NON-DEMENTED SUBJECTS WITH ALZHEIMER’S NEUROPATHOLOGY

Some individuals, here refereed to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their congitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s Disease (AD). In NDAN, unlike AD, toxic amyloid beta oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid beta in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanim(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The current work describes th…

Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

2021

LRP1-targeted St-Cl–polyglutamate conjugates as multivalent neuroprotective/neurotrophic therapeutics for Alzheimer’s disease.

Biomarkers Related to Synaptic Dysfunction to Discriminate Alzheimer’s Disease from Other Neurological Disorders

2022

Recently, the synaptic proteins neurogranin (Ng) and α-synuclein (α-Syn) have attracted scientific interest as potential biomarkers for synaptic dysfunction in neurodegenerative diseases. In this study, we measured the CSF Ng and α-Syn concentrations in patients affected by AD (n = 69), non-AD neurodegenerative disorders (n-AD = 50) and non-degenerative disorders (n-ND, n = 98). The concentrations of CSF Ng and α-Syn were significantly higher in AD than in n-AD and n-ND. Moreover, the Aβ42/Ng and Aβ42/α-Syn ratios showed statistically significant differences between groups and discriminated AD patients from n-AD patients, better than Ng or α-Syn…

Emerging contributions of formyl peptide receptors to neurodegenerative diseases.

2021

Abstract Inflammation is a central element of many neurodegenerative diseases. Formyl peptide receptors (FPRs) can trigger several receptor-dependent signal transduction pathways that play a key role in neuroinflammation and neurodegeneration. They are chemotactic receptors that help to regulate pro- and anti-inflammatory responses in most mammals. FPRs are primarily expressed in the immune and nervous systems where they interact with a complex pattern of pathogen-derived and host-endogenous molecules. Mounting evidence points towards a contribution of FPRs – via neuropathological ligands such as Amyloid beta, and neuroprotective ligands such as Humanin, Lipoxin A4, and Annexin A1 – to mult…