Peptides (v.23, #7)
Introduction by Joseph Kourie (1197).
Correlation between β-amyloid peptide production and human APP-induced neuronal death by Pascal Kienlen-Campard; Jean-Noël Octave (1199-1204).
The production of amyloid peptide (Aβ) from its precursor (APP) plays a key role in Alzheimer’s disease (AD). However, the link between Aβ production and neuronal death remains elusive. We studied the biological effects associated with human APP expression and metabolism in rat cortical neurons. Human APP expressed in neurons is processed to produce Aβ and soluble APP. Moreover, human APP expression triggers neuronal death. Pepstatin A, an inhibitor of aspartyl proteases that reduces Aβ production, protects neurons from APP-induced neurotoxicity. This suggests that Aβ production is likely to be the critical event in the neurodegenerative process of AD.
Keywords: Alzheimer’s disease; APP; Amyloid peptide; Neuronal death; Pepstatin A;
β-Amyloid (Aβ) protein in cerebrospinal fluid as a biomarker for Alzheimer’s disease by Niels Andreasen; Kaj Blennow (1205-1214).
With the arrival of symptomatic treatment (acetylcholine esterase inhibitors) and the promise of drugs that may delay disease progression, development of diagnostic biomarkers for Alzheimer’s disease (AD) are important. β-Amyloid (Aβ) protein is the main component of senile plaques. A marked reduction in cerebrospinal fluid (CSF)-Aβ42 in AD has been found in numerous studies. Importantly, reduced CSF-Aβ42 is also found very early in the disease process, before the onset of clinical symptoms. Recent studies suggest that CSF-Aβ42 have a satisfactory performance when used as a diagnostic marker for AD in clinical routine. This paper reviews CSF-Aβ42 as a biomarker for AD.
Keywords: Alzheimer’s disease (AD); β-Amyloid (Aβ); Biochemical markers; Cerebrospinal fluid (CSF); Plasma; Diagnosis;
Electrophysiologic properties of channels induced by Aβ25–35 in planar lipid bilayers by Meng-chin Allison Lin; Bruce L Kagan (1215-1228).
Aβ25–35, a fragment of the neurotoxic amyloid beta protein Aβ1–42 found in the brain of Alzheimer patients, possesses amyloidogenic, neurotoxins and channel forming abilities similar to that of Aβ1–42. We have previously reported that Aβ25–35 formed voltage-dependent, relatively nonselective, ion-permeable channels in planar lipid bilayers . Here, we show that Aβ25–35 formed channels in both solvent-containing and solvent-free bilayers. We also report that for Aβ25–35, channel forming activity was dependent on ionic strength, membrane lipid composition, and peptide concentration, but not on pH. Lower ionic strength and negatively charged lipids increased channel formation activity, while cholesterol decreased activity. The nonlinear function relating [Aβ25–35] and membrane activity suggests that aggregation of at least three monomers is required for channel formation.
Keywords: Membranes; Pores; Bilayers; Amyloid;
Laminin affects polymerization, depolymerization and neurotoxicity of Aβ peptide by Carlos Morgan; Manuel P Bugueño; Jorge Garrido; Nibaldo C Inestrosa (1229-1240).
Amyloid deposition in Alzheimer fibrils forms neurotoxic senile plaques in a process that may be modulated by associated proteins. In this work we demonstrate the ability of laminin-1 and laminin-2 to inhibit fibril formation and toxicity on cultured rat hippocampal neurons. We confirm that the laminin-1-derived peptide YFQRYLI inhibits efficiently both fibril formation and neurotoxicity and show that the IKVAV peptide inhibits amyloid neurotoxicity despite its slight inhibition of fibril formation. On other hand, laminin-1 induces disaggregation of preformed fibrils in vitro, characterized as a progressive disassembly of fibrils into protofibrils and further clearance of these latter species, leading to a continual inhibition of amyloid neurotoxicity.
Keywords: Alzheimer; Amyloid; Hippocampal neurons; Laminin; Neurotoxicity; Protofibrils;
Exogenous induction of cerebral β-amyloidosis in βAPP-transgenic mice by Lary C Walker; Michael J Callahan; Feng Bian; Robert A Durham; Alex E Roher; William J Lipinski (1241-1247).
A key commonality of most age-related neurodegenerative diseases is the accumulation of aggregation-prone proteins in the brain. Except for the prionoses, the initiation and propagation of these proteopathies in vivo remains poorly understood. In a previous study, we found that the deposition of the amyloidogenic peptide Aβ can be induced by injection of dilute extracts of Alzheimeric neocortex into the brains of Tg2576 transgenic mice overexpressing the human β-amyloid precursor protein. The present study was undertaken to assess the pathology after long-term (12 months) incubation, and to clarify the distinctive anatomical distribution of seeded Aβ-immunoreactivity. All mice were injected at 3 months of age; 5 months later, as expected, Aβ deposits were concentrated mostly in the injected hemisphere. After 12 months, abundant, transgene-derived Aβ deposits were present bilaterally in the forebrain, but plaque load was still clearly greater in the extract-injected hemisphere. There was also evidence of tau hyperphosphorylation in axons of the corpus callosum that had been injured by the injection, most prominently in transgenic mice, but also, to a lesser degree, in non-transgenic mice. Five months following injection of AD-extract, an isolated cluster of Aβ-immunoreactive microglia was sometimes evident in the ipsilateral entorhinal cortex; the strong innervation of the hippocampus by entorhinal cortical neurons suggests the possible spread of seeded pathology from the injection site via neuronal transport mechanisms. Finally, using India Ink to map the local dispersion of injectate, we found that Aβ induction is especially potent in places where the injectate is sequestered. The AD-seeding model can illuminate the emergence and spread of cerebral β-amyloidosis and tau hyperphosphorylation, and thus could enhance our understanding of AD and its pathogenic commonalties with other cerebral proteopathies.
Keywords: Alzheimer; Amyloid; Angiopathy; Aβ; Conformational disease; Neurodegeneration; Prion; Proteopathy; Senile plaque; Spongiform encephalopathy; Tau;
Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site by George Lee; Harvey B Pollard; Nelson Arispe (1249-1263).
Amyloid-β-protein (βA/4, AβP) accumulates in the brains of patients with Alzheimer’s disease (AD), regardless of genetic etiology, and is thought to be the toxic principle responsible for neuronal cell death. The ε4 allele of apoE has been linked closely to earlier onset of AD and increased deposition of the amyloid peptide, regardless of the clinical status of AD, while the apoE ε2 allele is generally protective. We have previously hypothesized that the cell target for amyloid peptide might be the apoptotic signal molecule phosphatidylserine (PS). We report here that annexin 5, a specific ligand for PS, not only blocks amyloid peptide AβP[1–40] cytotoxicity, but competitively inhibits AβP[1–40]-dependent aggregation of PS liposomes. In addition, we find that apoE2, but not apoE4, can not only perform the same protective effect on cells exposed to AβP[1–40], but can also competitively inhibit PS liposome aggregation and fusion by the amyloid peptide. Altogether, the in vivo and in vitro results reported here provide fundamental insight to the process by which amyloid targets specific neurons for destruction, and suggest that PS may be a surface “receptor” site for AβP binding. These results also provide a biochemical mechanism by which the apoE ε2 allele, but not apoE ε4, can be protective towards the incidence and progression of Alzheimer’s disease.
Keywords: Alzheimer’s disease; Amyloid-β-protein; Phosphatidylserine; Annexin 5; apoE; Cytotoxicity;
Imaging real-time aggregation of amyloid beta protein (1–42) by atomic force microscopy by Ashok Parbhu; Hai Lin; Julian Thimm; Ratneshwar Lal (1265-1270).
Amyloid beta protein (AβP) is the major fibrillar constituent of senile plaques. However, no causative role for AβP-fibers in Alzheimer’s disease (AD) pathology is established. Globular AβPs are continuously released during normal cellular metabolism at pico- to nano-molar concentration. We used atomic force microscopy (AFM) to examine aggregation of freshly prepared AβP1–42 and to examine the role of AβP concentration, imaging medium (air, water, or PBS) and agonists/antagonists on AβP-fibrillogenesis. At even very high and non-physiological AβP concentrations, 24–48 h of real-time AFM imaging (a) in water show only multiple layers of globular aggregates and no fibrils and (b) in PBS show mainly the globular structures and some short fibrils. On-line addition of Zn, an agonist for AβP-fibrillogenesis, induced a slow but non-fibrillar aggregation of globular AβPs. EDTA, a chelator of Zn and calcium (a modulator of AβP-mediated toxicity) induced a reversible change in the Zn-mediated aggregation. These results strongly suggest that no AβP-fibers are formed for the physiologically relevant concentration and thus the plaque-associated fibers may not account for the AD pathophysiology.
Keywords: Atomic force microscope; Amyloid beta protein; Fibrillogenesis; Protofibrils; AβP-fibrils; Alzheimer’s disease;
Amyloid β-peptide induces cholinergic dysfunction and cognitive deficits: a minireview by Manh Hung Tran; Kiyofumi Yamada; Toshitaka Nabeshima (1271-1283).
Amyloid β-peptide (Aβ) plays a critical role in the development of Alzheimer’s disease (AD). Much progress has been made in understanding this age-related neurodegenerative disorder, thus an insight into the cellular actions of Aβ and resulting functional consequences may contribute to preventive and therapeutic approaches for AD. In this review, recent evidence of Aβ-induced brain dysfunction, particularly of cholinergic impairment and memory deficits is summarized. Moreover, proposed mechanisms for Aβ-induced neurotoxicity such as oxidative stress, ion-channel formation, and Aβ-receptor interaction are discussed.
Keywords: Amyloid β-peptide; Alzheimer’s disease; Acetylcholine; Nicotinic acetylcholine receptor; Learning and memory; Oxidative stress;
Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides by Geneviève Evin; Andreas Weidemann (1285-1297).
Biochemical and genetic evidence indicates the balance of biogenesis/clearance of Aβ amyloid peptides is altered in Alzheimer’s disease. Aβ is derived, by two sequential cleavages, from the receptor-like amyloid precursor protein (APP). The proteases involved are β-secretase, identified as the novel aspartyl protease BACE, and γ-secretase, a multimeric complex containing the presenilins (PS). γ-Secretase can release either Aβ40 or the more aggregating and cytotoxic Aβ42. Secreted Aβ peptides become either degraded by the metalloproteases insulin-degrading enzyme (IDE) and neprilysin or metabolized through receptor uptake mediated by apolipoprotein E. Therapeutic approaches based on secretase inhibition or amyloid clearance are currently under development.
Keywords: Secretase; Protease; Protease inhibitors; Amyloid; Peptide vaccine; Presenilin; Alzheimer’s disease;
Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer’s amyloid β-peptide 1–42 by D.Allan Butterfield; Jaroslaw Kanski (1299-1309).
Amyloid β-peptide 1–42 [Aβ(1–42)] is central to the pathogenesis of Alzheimer’s disease (AD), and the AD brain is under intense oxidative stress. Our laboratory combined these two aspects of AD into the Aβ-associated free radical oxidative stress model for neurodegeneration in AD brain. Aβ(1–42) caused protein oxidation, lipid peroxidation, reactive oxygen species formation, and cell death in neuronal and synaptosomal systems, all of which could be inhibited by free radical antioxidants. Recent studies have been directed at discerning molecular mechanisms by which Aβ(1–42)-associated free radical oxidative stress and neurotoxicity arise. The single methionine located in residue 35 of Aβ(1–42) is critical for these properties. This review presents the evidence supporting the role of methionine in Aβ(1–42)-associated free radical oxidative stress and neurotoxicity. This work is of obvious relevance to AD and provides a coupling between the centrality of Aβ(1–42) in the pathogenesis of AD and the oxidative stress under which the AD brain exists.
Keywords: Amyloid; Methionine; Oxidative stress;
The channel hypothesis of Alzheimer’s disease: current status by Bruce L Kagan; Yutaka Hirakura; Rustam Azimov; Rushana Azimova; Meng-Chin Lin (1311-1315).
The channel hypothesis of Alzheimer’s disease (AD) proposes that the beta-amyloid (Aβ) peptides which accumulate in plaques in the brain actually damage and/or kill neurons by forming ion channels. Evidence from a number of laboratories has demonstrated that Aβ peptides can form ion channels in lipid bilayers, liposomes, neurons, oocyctes, and endothelial cells. These channels possess distinct physiologic characteristics that would be consistent with their toxic properties. Aβ channels are heterogeneous in size, selectivity, blockade, and gating. They are generally large, voltage-independent, and relatively poorly selective amongst physiologic ions, admitting calcium ion (Ca2+), Na+, K+, Cs+, Li+, and possibly Cl−. They are reversibly blocked by zinc ion (Zn2+), and tromethamine (tris), and irreversibly by aluminum ion (Al3+). Congo red inhibits channel formation, but does not block inserted channels. Although much evidence implicates Aβ peptides in the neurotoxicity of AD, no other toxic mechanism has been demonstrated to be the underlying etiology of AD. Channel formation by several other amyloid peptides lends credence to the notion that this is a critical mechanism of cytotoxicity.
Keywords: Pores; Membranes; Amyloid; Bilayers; Electrophysiology; Apoptosis;
Is γ-secretase a multienzyme complex for membrane protein degradation? by David H Small (1317-1321).
The β- and γ-secretases cleave the amyloid protein precursor (APP) to release the amyloid protein (Aβ). While the β-secretase has now been identified, the γ-secretase remains an enigma. A number of mutations in the presenilins (PS) and APP have been shown to alter the cleavage specificity of γ-secretase. However, the relationship between PS and γ-secretase remains unclear. This article presents some models of γ-secretase and suggests that the simplest interpretation of current data is that γ-secretase is a complex of several proteases located in the lumen of secretory vesicles.
Keywords: γ-Secretase; Multienzyme complex; Membrane protein degradation; Amyloid; Presenilin;
Glycosaminoglycans and β-amyloid, prion and tau peptides in neurodegenerative diseases by Javier Dı́az-Nido; Francisco Wandosell; Jesús Avila (1323-1332).
Protein aggregation into dense filamentous inclusions is a characteristic feature of many etiologically diverse neurodegenerative disorders including Alzheimer’s disease (AD), spongiform encephalopathies, and tauopathies. Thus, β-amyloid peptide (Aβ) accumulates within senile amyloid plaques in AD, protease-resistant prion protein constitutes the amyloid deposits in spongiform encephalopathies and tau protein gives rise to neurofibrillary tangles (NFT) both in AD and in tauopathies. Curiously, these abnormal protein inclusions contain, in addition to their major peptide components, some associated sulfated glycosaminoglycans (sGAG). Here we discuss the proposal that the binding of sGAG to aggregate-forming peptides may modify the pathogenic process depending on their subcellular localization.
Keywords: Alzheimer’s disease; Amyloid peptide; Neurodegenerative disease; Neurofibrillary tangle; Neuroprotection; Neurotoxicity; Prion disease; Protein aggregation; Proteoglycan; Spongiform encephalopathy; Sulfated glycosaminoglycan; Tau protein; Tauopathy;
The state versus amyloid-β: the trial of the most wanted criminal in Alzheimer disease by Catherine A Rottkamp; Craig S Atwood; James A Joseph; Akihiko Nunomura; George Perry; Mark A Smith (1333-1341).
Investigators studying the primary culprit responsible for Alzheimer disease have, for the past two decades, primarily focused on amyloid-β (Aβ). Here, we put Aβ on trial and review evidence amassed by the prosecution that implicate Aβ and also consider arguments and evidence gathered by the defense team who are convinced of the innocence of their client. As in all trials, the arguments provided by the prosecution and defense revolve around the same evidence, with opposing interpretations. Below, we present a brief synopsis of the trial for you, the jury, to decide the verdict. Amyloid-β: guilty or not-guilty?
Keywords: Alzheimer disease; Cell death; Neurodegeneration; Neurotoxicity; Oxidative stress; Phosphorylated tau;
Senile plaque composition and posttranslational modification of amyloid-β peptide and associated proteins by Craig S Atwood; Ralph N Martins; Mark A Smith; George Perry (1343-1350).
Amyloid deposits are primarily composed of the amyloid-β protein, although other proteins (and metal ions) also have been colocalized to these lesions. The pattern of oxidative modifications in amyloid plaques is very different to that associated with neurofibrillary tangles and neuronal cell bodies, likely reflecting the different composition of these structures, accessibility of oxidants, the generation of oxidants in and around these structures and the intrinsic antioxidant defense systems to protect these structures. Future studies directed at understanding Aβ interactions with other amyloid components, the role of oxidative modifications in stabilizing amyloid deposits and the determination of protease cleavage sites on Aβ may provide mechanistic insights regarding both amyloid formation and removal.
Keywords: Aβ; Alzheimer disease; Amyloid; Composition; Down syndrome; Inflammation; Metal ions; Microglial activation; Oxidants; Oxidative stress; Posttranslational modification; Protein crosslinks;
Transmissible spongiform encephalopathies: the story of a pathogenic protein by Bart Van Everbroeck; Philippe Pals; Jean-Jacques Martin; Patrick Cras (1351-1359).
An overview is provided from the first description of the transmissible spongiform encephalopathies (TSE) to recent major discoveries in this research field. The TSE are a group of diseases in animal and in man caused by a unique pathogen: the prion protein. The exact nature of the etiological agent or the prion protein is thought to be a misfolded protein. Although current research has provided a wealth of data indicating that a structural isoform of the prion protein is the responsible pathogen, this hypothesis is not yet experimentally proven.
Keywords: Prion protein; Kuru; Creutzfeldt–Jakob disease; Variant CJD; Bovine spongiform encephalopathy; BSE;