Search

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tins.2006.03.001 Byline: Christopher C.J. Miller, Declan M. McLoughlin, Kwok-Fai Lau, Maria E. Tennant, Boris Rogelj Abstract: Cerebral deposition of amyloid-[beta] peptide (A[beta]) within neuritic plaques is a hallmark pathology of Alzheimer's disease. It is now generally believed that the development of this pathology is central to the pathogenesis of Alzheimer's disease. As such, inhibiting A[beta] deposition or removing A[beta] deposits once they are formed represent therapeutic targets for Alzheimer's disease. A[beta] is derived from a precursor, the amyloid precursor protein (APP), and APP binds to the X11 family of adaptor proteins. Studies from several laboratories have now shown that X11[alpha] and X11[beta] (the two neuronal X11s) inhibit APP processing and A[beta] production. Exactly how this is achieved is not yet known but recent studies in which other X11 binding partners have been identified are beginning to reveal potential mechanisms. Author Affiliation: MRC Centre for Neurodegeneration Research, Departments of Neuroscience and Section of Old Age Psychiatry PO37, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE5 8AF, UK

X11α is a brain specific multi-modular protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). Aggregation of amyloid-β peptide (Aβ), an APP cleavage product, is believed to be central to the pathogenesis of Alzheimer's disease. Recently, overexpression of X11α has been shown to reduce Aβ generation and to ameliorate memory deficit in a transgenic mouse model of Alzheimer's disease. Therefore, manipulating the expression level of X11α may provide a novel route for the treatment of Alzheimer's disease. Human X11α is encoded by the gene APBA1. As evidence suggests that X11α expression can be regulated at transcription level, we have determined the gene structure and cloned the promoter of APBA1. APBA1 spans over 244 kb on chromosome 9 and is composed of 13 exons and has multiple transcription start sites. A putative APBA1 promoter has been identified upstream of exon 1 and functional analysis revealed that this is highly active in neurons. By deletion analysis, the minimal promoter was found to be located between −224 and +14, a GC-rich region that contains a functional Sp3 binding site. In neurons, overexpression of Sp3 stimulates the APBA1 promoter while an Sp3 inhibitor suppresses the promoter activity. Moreover, inhibition of Sp3 reduces endogenous X11α expression and promotes the generation of Aβ. Our findings reveal that Sp3 play an essential role in APBA1 transcription. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in elderly people, and the fourth most common cause of death in developed nations. Clinically, the disease is characterized by the deterioration of a patient’s cognitive and functional abilities, which may be accompanied by varying degrees of psychiatric and behavioural symptoms. The clinical decline is associated with a significant loss of neurons and synapses and ensuing neurochemical changes within the brain of an affected individual. In addition, two further microscopic pathologies are observed within the brain tissue: extracellular neuritic plaques and intracellular neurofibrillary tangles (NFTs). Both of these distinctive neuropathologies, regarded as hallmarks of the disease, are the result of abnormal aggregation of proteinaceous material. Neuritic plaques are largely formed from the aggregation of the 4 kDa β-amyloid peptide, which is released into the extracellular space following the metabolic breakdown of the larger amyloid precursor protein (APP). NFTs, which develop within neurons, are aggregates principally composed of the cytoskeletal protein tau and may be initiated by aberrant phosphorylation of tau. The prevailing view within the field is that mismetabolism of APP and abnormal production, aggregation and deposition of Aβ are central to the pathogenesis of AD, and that the Aβ pathology somehow leads to the tau/NFT pathology and the subsequent neuronal damage observed. In this article we review our current understanding of these molecular events and highlight how this knowledge is directing approaches to develop AD-modifying therapies. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is one of the most common causes of disability and death in the western world and as such it creates a tremendous strain on health service resources. In England alone the annual cost is now in the region of £1000 million. There are no specific treatments for AD as the pathogenesis is not yet fully understood. However, in the past decade our understanding of the molecular pathology of AD has been rapidly evolving, most dramatically so in the last few years. The promise is that a more complete understanding of the basic biology of the condition will enable therapies to be developed that treat the disorder itself and not just the symptoms.

Investigates the prolactin response to oral d-fenfluramine, a serotonin receptor, in elderly patients with late-onset Alzheimer's disease. Central serotonin responsivity in Alzheimer's disease.

Abstract The neuronal cyclin-dependent kinase p35/cdk5 comprises a catalytic subunit (cdk5) and an activator subunit (p35). To identify novel p35/cdk5 substrates, we utilized the yeast two-hybrid system to screen for human p35 binding partners. From one such screen, we identified β-catenin as an interacting protein. Confirmation that p35 binds to β-catenin was obtained by using glutathione S-transferase (GST)–β-catenin fusion proteins that interacted with both endogenous and transfected p35, and by showing that β-catenin was present in p35 immunoprecipitates. p35 and β-catenin also displayed overlapping subcellular distribution patterns in cells including neurons. Finally, we demonstrated that p35/cdk5 phosphorylates β-catenin. β-catenin also binds to presenilin-1 and altered β-catenin/presenilin-1 interactions may be mechanistic in Alzheimer's disease (AD). Abnormal p35/cdk5 activity has also been suggested to contribute to AD. We therefore investigated how modulation of p35/cdk5 activity influenced β-catenin/presenilin-1 interactions. Inhibition of p35/cdk5 with roscovitine did not alter the steady state levels of either β-catenin or presenilin-1 but reduced the amount of presenilin-1 bound to β-catenin. Thus, p35/cdk5 binds and phosphorylates β-catenin and regulates its binding to presenilin-1. The findings reported here therefore provide a novel molecular framework to connect p35/cdk5 with β-catenin and presenilin-1 in AD. [ABSTRACT FROM AUTHOR]

Abstract: Neurofilaments are the intermediate filaments of neurons and are synthesised in neuronal cell bodies and then transported through axons. Neurofilament light chain (NFL) is a principal component of neurofilaments, and phosphorylation of NFL head domain is believed to regulate the assembly of neurofilaments. However, the role that NFL phosphorylation has on transport of neurofilaments is poorly understood. To address this issue, we monitored axonal transport of phosphorylation mutants of NFL. We mutated four known phosphorylation sites in NFL head domain to either preclude phosphorylation, or mimic permanent phosphorylation. Mutation to preclude phosphorylation had no effect on transport but mutation of three sites to mimic permanent phosphorylation inhibited transport. Mutation of all four sites together to mimic permanent phosphorylation proved especially potent at inhibiting transport and also disrupted neurofilament assembly. Our results suggest that NFL head domain phosphorylation is a regulator of neurofilament axonal transport. [Copyright &y& Elsevier]

Abstract: The X11 protein family are multidomain proteins composed of a conserved PTB domain and two C-terminal PDZ domains. They are involved in formation of multiprotein complexes and two of the family members, X11α and X11β, are expressed primarily in neurones. Not much is known about the principal function of X11s, but through interactions with other neuronal proteins, they are believed to be involved in regulating neuronal signaling, trafficking and plasticity. Furthermore, they have been shown to modulate processing of APP and accumulation of Aβ, making them potential therapeutic targets for Alzheimer''s disease. This article reviews the known interactions of the different X11s and their involvement in Alzheimer''s disease. [Copyright &y& Elsevier]

Accumulation of cerebral amyloid β-protein (Aβ) is believed to be part of the pathogenic process in Alzheimer's disease. Aβ is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11β, a neuronal adaptor protein. X11β has been shown to inhibit the production of Aβ in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11β can also inhibit the deposition of Aβ as amyloid plaques is not known. Here we show that transgenic overexpression of X11β in neurons leads to a decrease in cerebral Aβ levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11β retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11β function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Mutations in the Presenilin 1 gene are the cause of the majority of autosomal dominant familial forms of Alzheimer''s disease. Presenilin 1 (PS1) is produced as a holoprotein but is then rapidly processed to amino- (N-PS1) and carboxy-terminal (C-PS1) fragments that are incorporated into stable high molecular mass complexes. The mechanisms that control PS1 cleavage and stability are not properly understood but sequences within C-PS1 have been shown to regulate both of these properties. Here we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates PS1 on threonine354 within C-PS1 both in vitro and in vivo. Threonine354 phosphorylation functions to selectively stabilize C-PS1. Our results demonstrate that cdk5/p35 is a regulator of PS1 metabolism. [Copyright &y& Elsevier]