Atish Mukerjee and Louis B. Hersh (Communicated by James Geddes)
Regulation of amyloid ß-peptide levels by enzymatic degradation
Abstract: It is generally accepted that amyloid ß peptides play a significant role in the etiology of Alzheimer’s disease. The Aß peptides are produced by the sequential cleavage of an amyloid precursor protein by a ß secretase followed by cleavage by a gamma secretase. The clearance of the Aß peptides appears to be due primarily by the action of one or more peptidases. An imbalance between the rate of synthesis and the rate of clearance of the Aß peptides is now considered a possible contributor to the onset of Alzheimer’s disease. This review focuses on peptidases that have been proposed to contribute to Aß peptide catabolism and discusses the evidence for their participation in Aß peptide clearance in vivo.
David H. Small and Lisa R. Fodero (Communicated by James Geddes)
Cholinergic regulation of synaptic plasticity as a therapeutic target in Alzheimer's disease
Abstract: There is increasing evidence for disturbances in nicotinic acetylcholine receptor (nAChR) function in Alzheimer’s disease (AD). nAChRs are involved in the regulation of many processes, including synaptic plasticity and memory. Levels of nAChRs are altered in the Alzheimer brain and there is evidence that the amyloid protein (Aß) can directly bind to nAChRs. Nicotinic agonists may also protect cells from Aß toxicity. Drugs which interact with the nAChR or which inhibit Aß binding to nAChRs may be of value for the treatment of AD.
Olga V Korchazhkina, Alison E Ashcroft, Tamas Kiss and Christopher Exley
The degradation of Aß25-35 by the serine protease plasmin is inhibited by aluminium
Abstract: The catabolism of amyloid beta peptides (Aß) may be important in their accumulation in the brain in both early and late-onset Alzheimer’s disease (AD). The serine protease plasmin is one of a suite of proteases implicated in AD. It is a promoter of alpha-cleavage of the amyloid ß precursor protein (AßPP) and will degrade Aß in vitro. Herein we have demonstrated cleavage of the amyloidogenic Aß25-35 by plasmin to produce the non-amyloidogenic fragment Aß29-35. The activity of plasmin was halved by pre-mixing it with aluminium (Al) prior to its addition to the peptide. An interaction between Al and proteases involved in the catabolism of Aß might define the putative link between Al and AD.
Xie Ling, RN Martins, M Racchi, S Craft, E Helmerhorst
Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor
Abstract: Amyloid ß (Aß) peptides are direct competitive inhibitors of insulin binding and action. We demonstrate that Aß peptides can inhibit the effect of insulin on the metabolic processing of the amyloid ß protein precursor (AßPP). As evidence emerges concerning the role of insulin and insulin like growth factors (IGFs) in learning and memory, recent findings have suggested that insulin may have a significant role in the pathogenetic pathways leading to Alzheimer's disease (AD). As an example several investigators have demonstrated upregulation of insulin receptors and defective insulin receptor signal transduction in AD brains. Moreover insulin has been shown to positively modulate AßPP proteolytic processing. The fact that insulin and Aß appear to share a common system for degradation and disposal as they are both substrates of the insulin degrading enzyme (IDE) suggested the possibility of a reciprocal interference. Here we report that Aß can directly interfere with insulin receptor signalling inhibiting the autophosphorylation of partially purified insulin receptors. As a consequence of such interaction we also demonstrate that Aß blocks the effect of insulin on the release of sAßPPalpha in chinese hamster ovaries (CHO) cells transfected with insulin receptors.
Gail V.W. Johnson and Craig D.C. Bailey (Communicated by James Geddes)
Tau, Where are We Now?
Abstract: Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. Tau is primarily a neuronal protein, but it is becoming increasingly evident that tau is present in non-neuronal cells where it also plays important roles. Tau is the primary protein component of the filaments (both paired helical and straight filaments) found in Alzheimer's disease brain. Further there is an ever growing family of neurodegenerative diseases called "tauopathies" where tau pathology is the primary, defining characteristic with little or no Aß pathology. These findings, along with the fact that mutations in the tau gene cause a group of diseases collectively known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), clearly demonstrate that tau dysfunction results in neuronal dysfunction and death. This review highlights recent findings concerning the normal metabolism and function of tau, as well as the abnormal processing and function of tau in Alzheimer's disease and in the tauopathies, both sporadic and familial.
Marina P. Sánchez, Isabel Gonzalo, Jesús Ávila, Justo García de Yébenes (Communicated by Javier Diaz-Nido)
Progressive supranuclear palsy and tau hyperphosphorylation in a patient with a C212Y parkin mutation
Abstract: Autosomal recessive-juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson’s disease (PD) and is related to mutations in the Park-2 gene, encoding for a protein ligase of ubiquitin, parkin. Different mutations located along the parkin gene have been observed in different AR-JP affected families, possibly interfering with the normal function of parkin and the proteasome system. Two cases of patients with AR-JP have been recently described presenting different homo- and heterozygous parkin mutations and limited tau pathology. We report here the case of a patient with clinical and pathological findings compatible with progressive supranuclear palsy (PSP), carrier of a single, heterozygous mutation of the parkin gene, and homozygous for the H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation has been observed in our patient brain samples, suggesting that a partial deficit of parkin, a protein with ubiquitin-ligase function, may trigger tau pathology in individuals with molecular genetic risk factors.
Tadanobu Utsuki, Mohammed Shoaib, Harold W. Holloway, Donald K. Ingram, William C. Wallace,Vahram Haroutunian, Kumar Sambamurti, Debomoy K. Lahiri, Nigel H. Greig
Nicotine Lowers the Secretion of the Alzheimer’s Amyloid ß-Protein Precursor that Contains Amyloid ß-Peptide in Rat
Abstract: Reports of an inverse relationship between nicotine intake, due to cigarette smoking, and the incidence of Alzheimer’s disease (AD) prompted us to investigate the effects of nicotine on amyloid ß-protein precursor (AßPP) processing in rat. Over-production and/or altered metabolism of AßPP, resulting in increased amyloid ß-peptide (Aß), appear pivotal in the pathogenesis of AD. Aß is generated proteolytically from AßPP by a group of secretases. AßPP cleavage by gamma–secretase results in the secretion of a truncated soluble AßPP (sAPPg) that contains intact Aß. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking and a higher but well tolerated dose, respectively, was administered over 14 days and Western blot analysis was performed on sAPP fragments. Both doses significantly reduced sAPPg. These actions were blocked by nicotinic receptor antagonism. Whereas nicotinic antagonists alone had no effect on either total sAPP or sAPPg levels in CSF, muscarinic antagonism significantly elevated them; suggesting that muscarinic rather than nicotinic receptor silence alters processing of AßPP to favor a potentially amyloidogenic route. Combined nicotine and muscarinic antagonism attenuated the action of the latter to elevate sAPPg, indicating that nicotine modifies AßPP processing away from potentially amyloidogenic products. These results suggest that within the brain, levels of total sAPP, sAPPg and, accordingly, Aß are subject to cholinergic manipulation, offering therapeutic potential at the level of AßPP processing to decrease Aß deposition.
Carola Otth, Ilona I. Concha, Thomas Arendt, Jens Stieler, Reinhard Schliebs, Christian González-Billault, Ricardo B. Maccioni
AßPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576
Abstract: Previous studies of Aß-induced neuronal damage of hippocampal cells in culture have provided strong evidence that deregulation of the Cdk5/p35 kinase system is involved in the neurodegeneration pathway. Cdk5 inhibitors and antisense probes neuroprotected hippocampal cells against the neurotoxic action of Aß. To further investigate the mechanisms underlying the participation of Cdk5 in neuronal degeneration, the transgenic mouse containing the Swedish mutations, Tg2576, was used as an animal model. Immunocytochemical studies using anti-Aß(1-17) antibody evidenced the presence of labeled small-clustered core plaques in the hippocampus and cortex of 18-month-old transgenic mice brains. The loss of granular cells without a compressed appearance was detected in the vicinity of the cores in the dentate gyrus of the hippocampus. Immunostaining of Tg2576 brain sections with antibodies to AT8, PHF1 and GFAP labeled punctuate dystrophic neurites in and around the amyloid core. Reactive astrocytosis around the plaques in the hippocampus was also observed. Studies at the molecular level showed differences in the expression of the truncated Cdk5 activator p25 in the transgenic animal, as compared with wild type controls. However no differences in Cdk5 levels were detected, thus corroborating previous cellular findings. Interestingly, hyperphosphorylated tau epitopes were substantially increased as assessed with the AT8 and PHF1 antibodies, in agreement with the observation of a p25 increase in the transgenic animal. These observations strongly suggest that the increased exposure of Alzheimer´s type tau phosphoepitopes in the transgenic mice correlated with deregulation of Cdk5 leading to an increase in p25 levels. These studies also provide further evidence on the links between extraneuronal amyloid deposition and tau pathology.
Alex E. Roher, Tyler A. Kokjohn
Commentary: Of mice and men: the relevance of transgenic mice Aß immunizations to Alzheimer’s disease
Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a time-dependent amyloid fibril deposition in cortical senile plaques and cerebral vascular walls. Several transgenic (Tg) mice have been engineered to overexpress amyloid-beta precursor protein (AßPP) with familial AD mutations. With advancing age, the Tg mice accumulate amyloid-beta (Aß) peptides, primarily of 40 to 42 amino acids, in plaques and blood vessel wall deposits which resemble morphologically those characteristic of AD. Immunizing Tg mice with Aß peptides or infusion of anti-Aß antibodies resulted in a remarkable Aß load decrease and reversal of cognitive dysfunction in these animals. These observations led to immediate efforts to employ similar therapeutic protocols in AD patients. However, Tg hAßPP-overexpressing mice differ from AD patients in several important biochemical, anatomical, pathological and temporal aspects. These fundamental differences must be considered when extrapolating Tg mice Aß vaccination experimental observations to AD.
Transcript of Live Discussion held at the Alzheimer Research Forum
From Epidemiology to Therapeutic Trials with Anti-Inflammatory Drugs in Alzheimer’s Disease: The Role of NSAIDs and Cyclooxygenase in ß-Amyloidosis and Clinical Dementia