The role of amyloid β peptide 42 in Alzheimer’s disease

Satori Pharmaceuticals Incorporated, 222 Berkeley Street, Suite 1040, Boston, MA 02116, USA.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 12/2007; 116(2):266-86. DOI: 10.1016/j.pharmthera.2007.06.006
Source: PubMed


During the last 20 years, an expanding body of research has elucidated the central role of amyloid precursor protein (APP) processing and amyloid beta peptide (Abeta) production in the risk, onset, and progression of the neurodegenerative disorder Alzheimer's disease (AD), the most common form of dementia. Ongoing research is establishing a greater level of detail for our understanding of the normal functions of APP, its proteolysis products, and the mechanisms by which this processing occurs. The importance of this processing machinery in normal cellular function, such as Notch processing, has revealed specific concerns about targeting APP processing for therapeutic purposes. Aspects of AD that are now well studied include direct and indirect genetic and other risk factors for AD, APP processing, and Abeta production. Emerging from these studies is the particular importance of the long form of Abeta, Abeta42. Elevated Abeta42 levels, as well as particularly the elevation of the ratio of Abeta42 to the shorter major form Abeta40, has been identified as important in early events in the pathogenesis of AD. The specific pathological importance of Abeta42 has drawn attention to seeking drugs that will selectively lower the levels of this peptide through reduced production or increased clearance while allowing normal protein processing to remain substantially intact. An increasing variety of compounds that modulate APP processing to reduce Abeta levels are being identified, some with Abeta42 selectivity. Such compounds are now reaching clinical evaluation to determine how they may be of benefit in the treatment of AD.

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    • "In our study we decided to investigate the early phase of Aβ42 self-assembly. We chose Aβ42 because the elevation of its levels and of the ratio of Aβ42 to the shorter major form Aβ40, had been identified as important early events in the pathogenesis of AD[31]. Specific questions to be addressed are: what is the size of the smallest detectable oligomer in solution, and do well-defined, oligomeric species exist as the hypothesis of a toxic oligomer might suggest . "
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    ABSTRACT: Alzheimer's disease (AD)-associated amyloid β peptide (Aβ) is one of the main actors in AD pathogenesis. Aβ is characterized by its high tendency to self-associate, leading to the generation of oligomers and amyloid fibrils. The elucidation of pathways and intermediates is crucial for the understanding of protein assembly mechanisms in general and in conjunction with neurodegenerative diseases, e.g., for the identification of new therapeutic targets. Our study focused on Aβ42 and its oligomeric assemblies in the lag phase of amyloid formation, as studied by sedimentation velocity (SV) centrifugation. The assembly state of Aβ during the lag phase, the time required by an Aβ solution to reach the exponential growth phase of aggregation, was characterized by a dominant monomer fraction below 1 S and a population of oligomeric species between 4 and 16 S. From the oligomer population, two major species close to a 12-mer and an 18-mer with a globular shape were identified. The recurrence of these two species at different initial concentrations and experimental conditions as the smallest assemblies present in solution supports the existence of distinct, energetically favored assemblies in solution. The sizes of the two species suggest an Aβ42 aggregation pathway that is based on a basic hexameric building block. The study demonstrates the potential of SV analysis for the evaluation of protein aggregation pathways.
    No preview · Article · May 2015 · PLoS ONE
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    • "Indeed, data showed that i.c.v. administration of incubated Aβ in mice/rats could induce memory deficits, inhibit LTP, and lead to oxidative stress and neuronal loss [32, 33]. Additionally, this model is rather suitable and efficient to test compounds which could act at early stages of AD. "
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    ABSTRACT: The effects of xanthoceraside on learning and memory impairment were investigated and the possible mechanism associated with the protection of mitochondria was also preliminarily explored in Alzheimer's disease (AD) mice model induced by intracerebroventricular (i.c.v.) injection of Aβ1-42. The results indicated that xanthoceraside (0.08-0.32 mg/kg) significantly improved learning and memory impairment in Morris water maze test and Y-maze test. Xanthoceraside significantly reversed the aberrant decrease of ATP levels and attenuated the abnormal increase of ROS levels both in the cerebral cortex and hippocampus in mice injected with Aβ1-42. Moreover, xanthoceraside dose dependently reversed the decrease of COX, PDHC, and KGDHC activity in isolated cerebral cortex mitochondria of the mice compared with Aβ1-42 injected model mice. In conclusion, xanthoceraside could improve learning and memory impairment, promote the function of mitochondria, decrease the production of ROS, and inhibit oxidative stress. The improvement effects on mitochondria may be through withstanding the damage of Aβ to mitochondrial respiratory chain and the key enzymes in Kreb's cycle. Therefore, the results from present study and previous study indicate that xanthoceraside could be a competitive candidate for the treatment of AD.
    Full-text · Article · May 2014 · Evidence-based Complementary and Alternative Medicine
    • "Soluble spherical aggregates of A1-40 and A1-42 produced in vitro are both toxic, but the latter are much more so, by a factor of about 100, and their toxicity may involve tau protein kinase I/glycogen synthase kinase-3 activation . The severity of the cognitive defect in AD correlates with levels of oligomers in the brain, not the total A burden [2] [4]. "
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    ABSTRACT: Targeting of the central nervous system (CNS) in order to treat disorders is actually challenging due to the necessity to cross the blood brain barrier (BBB). This review aims to show how nanomedicine can propose new approach for the treatment and the diagnosis of CNS diseases focusing on Alzheimer's disease (AD). AD is a neurodegenerative disorder prevalent in the senile population. It is characterized by severe neuronal loss and proliferation of plaques composed of β-amyloid peptide (Aβ) and Tau protein deposites. An imbalance between production and clearance leading to the aggregation of Aβ peptides especially in neurotoxic forms, may be the initiating factor in AD. The absence of an effective therapeutic approach nowadays could be, in part, due to the bad knowledge of AD physiopathology and the lack of early diagnosis. Many drawbacks such as poor bioavailability or limited BBB arising of tested molecules in the current or new therapeutic strategies explain their failure but can be resolved by the use of nanotechnology. Examples of recently published works using nanoparticles for improving diagnosis and therapy of AD are presented. Ideal nanocarriers for this aim must be able to pass through the BBB and to interact with an AD marker as soluble extracellular Aβ forms which are known as the most toxic ones. These first results, even if many ones were obtained in vitro, brought to light the potential of nanoparticles for this challenging issue.
    No preview · Article · Jul 2013 · Annales Pharmaceutiques Françaises
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