Impaired apoptosis in lymphoblasts from Alzheimer’s disease patients: Cross-talk of Ca<Superscript>2+</Superscript>/calmodulin and ERK1/2 signaling pathways

We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer’s disease (AD) patients to escape from serum deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca²⁺/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2 pathway setting by Ca²⁺/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic factor withdrawal. F. Bartolomé, N. de las Cuevas: These authors contributed equally to this work. Received 14 February 2007; received after revision 16 April 2007; accepted 23 April 2007     

Simvastatin overcomes the resistance to serum withdrawal-induced apoptosis of lymphocytes from Alzheimer’s disease patients

Statins may exert beneficial effects on Alzheimer’s disease (AD) patients. Based on the antineoplastic and apoptotic effects of statins in a number of cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle and/or apoptosis. A growing body of evidence indicates that neurodegeneration involves the cell-cycle activation in postmitotic neurons. Failure of cell-cycle control is not restricted to neurons in AD patients, but occurs in peripheral cells as well. For these reasons, we studied the role of simvastatin (SIM) on cell survival/death in lymphoblasts from AD patients. We report here that SIM induces apoptosis in AD lymphoblasts deprived of serum. SIM interacts with PI3K/Akt and ERK1/2 signaling pathways thereby decreasing the serum withdrawal-enhanced levels of the CDK inhibitor p21^Cip1 (p21) and restoring the vulnerability of AD cells to trophic factor deprivation.     

Trypsin and trypsin-like proteases in the brain: Proteolysis and cellular functions

Several serine proteases including thrombin, tissue-type plasminogen activator and urokinase-type plasminogen activator have been well characterized in the brain. In this article, we review the brain-related trypsin and trypsin-like serine proteases. Accumulating evidence demonstrates that trypsin and trypsin-like serine proteases play very important roles in neural development, plasticity, neurodegeneration and neuroregeneration in the brain. Neuropsin is able to hydrolyze the extracellular matrix components by its active site serine, and regulates learning and memory in normal brain. The mutant neurotrypsin contributes to mental retardation in children. Neurosin seems to be involved in the pathogenesis of neurodegenerative disorders, like Alzheimer’s disease, Parkinson’s disease or multiple sclerosis. Although mesotrypsin/trypsin IV is also implicated in neurodegeneration, its functional significance still remains largely unknown. Particularly, mesotrypsin/trypsin IV, P22 and neurosin exert their physiological and pathological functions through activation of certain protease-activated receptors (PARs). In the brain, the presence of serpins controls the activity of serine proteases. Therefore, understanding the interaction among brain trypsin, serpins and PARs will provide invaluable tools for regulating normal brain functions and for the clinical treatment of neural disorders. Y. Wang, W. Luo: These authors made equal contributions. Received 26 June 2007; received after revision 13 August 2007; accepted 12 September 2007     

Synphilin-1 isoforms in Parkinson’s disease: regulation by phosphorylation and ubiquitylation

Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia nigra pars compacta. The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which α-synuclein represents their major component. α-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells, synphilin-1 forms inclusions together with α-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various E3 ubiquitin-ligases, such as SIAH, parkin and dorfin. Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone and accumulates in detergent-insoluble fractions of brains from α-synucleinopathy patients. Synphilin-1A inclusions recruit both α-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss several aspects of the neurobiology and pathology of synphilin-1 isoforms, focusing on possible implications for PD. Received 26 July 2007; received after revision 19 September 2007; accepted 15 October 2007     

Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease

Deposition of amyloid β-protein (Aβ) in the brain is an early and invariant neuropathological feature of Alzheimer’s disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Aβ in the brain. Here, we review four anti-amyloidogenic strategies: (i) reduction of Aβ production, which has mainly been approached with secretase inhibition, (ii) promotion of the Aβ degrading catabolic pathway, including an Aβ degrading enzyme, neprilysin, (iii) immunotherapy for Aβ and (iv) inhibition of Aβ aggregation. We have reported that AD patients have a favorable molecular environment for Aβ aggregation and that various compounds, such as polyphenols, interfere with Aβ aggregation and destabilize preformed Aβ fibrils. Received 21 December 2005; received after revision 14 February 2006; accepted 29 March 2006     

Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease

The identification of the aspartic protease BACE1 (β-secretase) was a defining event in research aimed at understanding the molecular mechanisms that underlie Alzheimer’s disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting step in the production of amyloid-β (Aβ) the principal component of plaque pathology in AD, the excessive production of which is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that genetic deletion of BACE1 completely abolishes Aβ production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target in blocking aberrant Aβ production in AD. Received 15 May 2008; received after revision 13 June 2008; accepted 18 June 2008     

Common features between diabetes mellitus and Alzheimer’s disease

Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic properties are beneficial for both T2DM and AD. Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009     

Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review, we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt, Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD. Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006     

The molecular link between β- and γ-secretase activity on the amyloid β precursor protein

Alzheimer’s disease (AD) is characterized by an accumulation in the brain of amyloid β peptides (Aβ). The production of Aβ requires two sequential cleavages induced by β- and γ-secretases on the β-amyloid precursor protein (APP). Altered activity of these secretases is involved in the pathogenesis of AD. The expression and activity of β-secretase (BACE1) is augmented in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD), alters the activity of γ-secretase, leading to increased production of Aβ42. Here we review the role of oxidative stress as a molecular link between the β- and the γ-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying PS1 mutations.     

Molecular pathogenesis of apolipoprotein E-mediated amyloidosis in late-onset Alzheimer’s disease

Apolipoprotein E (apoE) ɛ4 allele is a genetic risk factor for late-onset familial and sporadic Alzheimer’s disease (AD). In the central nervous system, apoE is secreted mainly by astrocytes as a constituent of high-density lipoproteins. A recent study using apoE knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid β protein (Aβ). However, no clear explanation of the pathogenesis of apoE-induced AD has been provided. Here we discuss two possible mechanisms by which apoE might enhance Aβ deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces lysosomal accumulation of Aβ and amyloidogenic APP (amyloid precursor protein) fragments, leading to neuronal death. The other is the extracellular pathway in which apoE-containing lipoproteins are trapped by Aβ1–42 deposits mobilizing soluble Aβ peptides and consequently enlarge amyloid plaques. These two mechanisms may operate at different stages of AD pathogenesis and suggest a chaperone-like function for the apoE molecule. Received 4 February 1999; received after revision 9 April 1999; accepted 23 April 1999     

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with an emphasis on the functional role of presenilins in cell biology. Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008     

The role of inflammation in sporadic and familial Parkinson’s disease

The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions.     

Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons

Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent major dementia-associated abnormalities in Alzheimer’s disease (AD). This study examined the role of oxidative stress as a factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated with H₂O₂ (9–90 μM) or desferrioxamine (2–25 μM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function, and pro-apoptosis and sprouting gene expression. H₂O₂ treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The H₂O₂-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin, and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection), and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast, hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD, both oxidative stress and hypoxic injury can contribute to AD neurodegeneration. Received 24 May 2000; received after revision 7 July 2000; accepted 27 July 2000     

Polyphenolic phytochemicals – just antioxidants or much more?

Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles. A ‘recommended’ human diet contains significant quantities of polyphenolics, as they have long been assumed to be ‘antioxidants’ that scavenge excessive, damaging, free radicals arising from normal metabolic processes. There is recent evidence that polyphenolics also have ‘indirect’ antioxidant effects through induction of endogenous protective enzymes. There is also increasing evidence for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation. Inductive or signalling effects may occur at concentrations much lower than required for effective radical scavenging. Over the last 2 – 3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics. We summarise the current knowledge of the intake, bio-availability and metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects and regulatory effects on energy metabolism and gut health. Received 14 May 2007; received after revision 27 June 2007; accepted 24 July 2007     

Nutrigenomics in the whole-genome scanning era: Crohn’s disease as example

Nutrigenomics has the potential to tailor diets to optimize health, based on knowledge of key genetic polymorphisms. Identification of candidate genes is often based on a priori knowledge of disease processes. However, genome-wide association methods are not only validating previously identified genes and polymorphisms, but also revealing new gene-disease associations not anticipated from prior knowledge. In Crohn’s disease (CD), such studies not only confirm the importance of caspase-activated recruitment domain 15 and major histocompatability complex II molecules, but also reveal strong associations with the proinflammatory cytokine interleukin-23 receptor and autophagy-related 16-like gene. Genes identified to date in CD can be linked into two interrelated pathways: receptor-mediated cytokine induction or autophagocytosis. New genomic technologies need to be matched with innovative methodologies to characterize the likely impact of foods and to take the field to another dimension of value for human diet development and optimized health. Received 2 July 2007; received after revision 31 July 2007; accepted 29 August 2007     

Etiologic factors in Paget’s disease of bone

Paget’s disease of bone is a chronic focal skeletal disorder characterized by increased bone resorption by the osteoclasts. Paramyxoviral gene products have been detected in pagetic osteoclasts. Paget’s disease is an autosomal dominant trait with genetic heterogeneity. Several mutations in the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) have been identified in patients with Paget’s disease. Similarly, mutations in the valosin-containing protein (VCP) gene have been shown to cause inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia. In addition, gene polymorphisms and enhanced levels of cytokine/growth factors associated with Paget’s disease have been identified. However, the etiologic factors in Paget’s disease remain elusive. A cause and effect relationship for the paramyxoviral infection and SQSTM1/ p62 gene mutations responsible for pagetic osteoclast development and disease severity are unclear. This article will highlight the etiologic factors involved in the pathogenesis of Paget’s disease. Received 6 October 2005; received after revision 2 November 2005; accepted 24 November 2005     

Caffeine analogs: biomedical impact

Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer’s disease, asthma, cancer, diabetes, and Parkinson’s disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms. Received 31 January 2007; received after revision 7 April 2007; accepted 26 April 2007     

Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer’s disease

Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved in the pathogenesis of Alzheimer’s disease (AD). RAGE is a receptor for amyloid β peptides (Aβ), mediates Aβ neurotoxicity and also promotes Aβ influx into the brain and contributes to Aβ aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform, acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain AD development by reducing Aβ transport into the brain and Aβ production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.     

Mitochondrial association of alpha-synuclein causes oxidative stress

α-Synuclein is a neuron-specific protein that contributes to the pathology of Parkinson’s disease via mitochondria-related mechanisms. The present study investigated possible interaction of α-synuclein with mitochondria and consequences of such interaction. Using SHSY cells overexpressing α-synuclein A53T mutant or wild-type, as well as isolated rat brain mitochondria, the present study shows that α-synuclein localizes at the mitochondrial membrane. In both SHSY cells and isolated mitochondria, interaction of α-synuclein with mitochondria causes release of cytochrome c, increase of mitochondrial calcium and nitric oxide, and oxidative modification of mitochondrial components. These findings suggest a pivotal role for mitochondria in oxidative stress and apoptosis induced by α-synuclein. Received 27 December 2007; received after revision 7 February 2008; accepted 8 February 2008