Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer’s disease

Alzheimer's disease (AD) is characterized by increases in amyloid-beta (Abeta) peptides, neurofibrillary tangles, oxidative stress and cholinergic deficits. However, the selectivity of these deficits and their relation with the Abeta pathology or oxidative stress remain unclear. We therefore investigated amyloidosis-related changes in acetylcholine (ACh) and serotonin (5-HT) innervations of hippocampus and parietal cortex by quantitative choline acetyltransferase (ChAT) and 5-HT immunocytochemistry, in 6, 12/14 and 18 month-old transgenic mice carrying familial AD-linked mutations (hAPP(Sw,Ind)). Further, using manganese superoxide dismutase (MnSOD) and nitrotyrosine immunoreactivity as markers, we evaluated the relationship between oxidative stress and the ACh deficit in 18 month-old mice. Thioflavin-positive Abeta plaques were seen in both regions at all ages; they were more numerous in hippocampus and increased in number (>15-fold) and size as a function of age. A majority of plaques exhibited or were surrounded by increased MnSOD immunoreactivity, and dystrophic ACh or 5-HT axons were seen in their immediate vicinity. Counts of immunoreactive axon varicosities revealed significant decreases in ACh innervation, with a sparing of the 5-HT, even in aged mice. First apparent in hippocampus, the loss of ACh terminals was in the order of 20% at 12/14 months, and not significantly greater (26%) at 18 months. In parietal cortex, the ACh denervation was significant at 18 months only, averaging 24% across the different layers. Despite increased perivascular MnSOD immunoreactivity, there was no evidence of dystrophic ACh varicosities or their accentuated loss in the perivascular area. Moreover, there was virtually no sign of tyrosine nitration in ChAT nerve terminals or neuronal cell bodies. These data suggest that aggregated Abeta exerts an early, non-selective and focal neurotoxic effect on both ACh and 5-HT axons, but that a selective, plaque- and oxidative stress-independent diffuse cholinotoxicity, most likely caused by soluble Abeta assemblies, is responsible for the hippocampal and cortical ACh denervation.

[1]  J. S. McCasland,et al.  GAP-43 Is Critical for Normal Development of the Serotonergic Innervation in Forebrain , 2002, The Journal of Neuroscience.

[2]  L. Lue,et al.  Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease , 1999 .

[3]  S. Leurgans,et al.  Loss of basal forebrain P75NTR immunoreactivity in subjects with mild cognitive impairment and Alzheimer's disease , 2002, The Journal of comparative neurology.

[4]  W. Benzing,et al.  Galaninergic innervation of the cholinergic vertical limb of the diagonal band (Ch2) and bed nucleus of the stria terminalis in aging, Alzheimer's disease and Down's syndrome. , 1993, Dementia.

[5]  Guiquan Chen,et al.  A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease , 2000, Nature.

[6]  H. Ischiropoulos,et al.  Detection and quantitation of nitrotyrosine residues in proteins: in vivo marker of peroxynitrite. , 1996, Methods in enzymology.

[7]  M J Ball,et al.  beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  E. Hamel,et al.  Cholinergic basal forebrain neurons project to cortical microvessels in the rat: electron microscopic study with anterogradely transported Phaseolus vulgaris leucoagglutinin and choline acetyltransferase immunocytochemistry , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  V. Chan‐Palay,et al.  Distribution of altered hippocampal neurons and axons immunoreactive with antisera against neuropeptide Y in Alzheimer's‐type dementia , 1986, The Journal of comparative neurology.

[10]  L. Launer,et al.  Cerebral amyloid angiopathy and cognitive function: The HAAS autopsy study , 2002, Neurology.

[11]  R. Nicoll,et al.  Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Mikkelsen,et al.  Amyloid beta neurotoxicity in the cholinergic but not in the serotonergic phenotype of RN46A cells. , 1998, Brain research. Molecular brain research.

[13]  J. O'Brien,et al.  Cognitive deficit induced by acute tryptophan depletion in patients with Alzheimer's disease. , 2000, The American journal of psychiatry.

[14]  P. A. Peterson,et al.  β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity , 2000, The Journal of Biological Chemistry.

[15]  L. Descarries,et al.  Serotonin innervation in adult rat neostriatum. I. Quantified regional distribution , 1987, Brain Research.

[16]  R. Nitsch,et al.  Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils , 2001, Science.

[17]  R. Kalaria.  Cerebrovascular Degeneration Is Related to Amyloid‐β Protein Deposition in Alzheimer's Disease a , 1997 .

[18]  R. Quirion,et al.  Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. , 2002, Progress in neurobiology.

[19]  L. Descarries,et al.  Comparative analysis of cholinergic innervation in the dorsal hippocampus of adult mouse and rat: A quantitative immunocytochemical study , 2002, Hippocampus.

[20]  P. Kelly,et al.  Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis , 2002, The Journal of Neuroscience.

[21]  C. Masters,et al.  Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease , 1999, Annals of neurology.

[22]  M. Scheunemann,et al.  Alterations in cholinergic and non-cholinergic neurotransmitter receptor densities in transgenic Tg2576 mouse brain with β-amyloid plaque pathology , 2003, International Journal of Developmental Neuroscience.

[23]  L. Mucke,et al.  Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease , 1997, Nature.

[24]  R. Schliebs,et al.  Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human β-amyloid precursor protein , 2002, Brain Research.

[25]  S. Rapoport,et al.  Beta-amyloid induced increase in choline flux across PC12 cell membranes , 1997, Neuroscience Letters.

[26]  L. Mucke,et al.  Modulation of Alzheimer-Like Synaptic and Cholinergic Deficits in Transgenic Mice by Human Apolipoprotein E Depends on Isoform , Aging, and Overexpression of Amyloid β Peptides But Not on Plaque Formation , 2002, The Journal of Neuroscience.

[27]  N. Robakis,et al.  Immunohistochemical evidence of antioxidant stress in Alzheimer's disease , 1992 .

[28]  T. Arendt,et al.  Degeneration of β-amyloid-associated cholinergic structures in transgenic APPSW mice , 2003, Brain Research.

[29]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[30]  Joseph S. Beckman,et al.  Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease , 1997, The Journal of Neuroscience.

[31]  T. Bliss,et al.  Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice , 1999, Nature Neuroscience.

[32]  G. Huber,et al.  Apoptotic cell death induced by beta-amyloid 1-42 peptide is cell type dependent. , 1995, Journal of neurochemistry.

[33]  A. Sahgal,et al.  The role of serotonergic-cholinergic interactions in the mediation of cognitive behaviour , 1995, Behavioural Brain Research.

[34]  T. Maeda,et al.  Postnatal development of serotonin nerve fibers in the somatosensory cortex of mice studied by immunohistochemistry , 1986, The Journal of comparative neurology.

[35]  J. Hardy,et al.  The Alzheimer family of diseases: many etiologies, one pathogenesis? , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Estus,et al.  Aggregated Amyloid-β Protein Induces Cortical Neuronal Apoptosis and Concomitant “Apoptotic” Pattern of Gene Induction , 1997, The Journal of Neuroscience.

[37]  D. Selkoe,et al.  Alzheimer's Disease--Genotypes, Phenotype, and Treatments , 1997, Science.

[38]  Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease. , 1999 .

[39]  J. Hallenbeck,et al.  Brain Vessels Normally Undergo Cyclic Activation and Inactivation: Evidence from Tumor Necrosis Factor-α, Heme Oxygenase-1, and Manganese Superoxide Dismutase Immunostaining of Vessels and Perivascular Brain Cells , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  K. Davis,et al.  Neurochemical Correlates of Dementia Severity in Alzheimer's Disease: Relative Importance of the Cholinergic Deficits , 1995, Journal of neurochemistry.

[41]  D. Selkoe.  Alzheimer's disease: genotypes, phenotypes, and treatments. , 1997, Science.

[42]  Xudong Huang,et al.  Redox‐Active Metals, Oxidative Stress, and Alzheimer's Disease Pathology , 2004, Annals of the New York Academy of Sciences.

[43]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[44]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[45]  G. Huber,et al.  Apoptotic Cell Death Induced by β‐Amyloid1–42 Peptide Is Cell Type Dependent , 1995 .

[46]  M. Buhot,et al.  Role of serotonin in memory impairment , 2000, Annals of medicine.

[47]  B. Sommer,et al.  Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[48]  R. Quirion,et al.  Amyloid β‐Peptide Inhibits High‐Affinity Choline Uptake and Acetylcholine Release in Rat Hippocampal Slices , 1998 .

[49]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[50]  Jörg Lindenau,et al.  Cellular distribution of superoxide dismutases in the rat CNS , 2000, Glia.

[51]  Sebastian Pascarelle,et al.  Unusual spectral energy distribution of a galaxy previously reported to be at redshift 6.68 , 2000, Nature.

[52]  T. Hökfelt,et al.  Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F β-amyloid precursor protein — initial observations , 2000, Neuroscience.

[53]  D. Butterfield,et al.  Alzheimer’s amyloid β-peptide (1–42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide , 2004, Neurobiology of Aging.

[54]  M. Smith,et al.  Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. , 1998, The American journal of pathology.

[55]  K. Duff,et al.  Reorganization of Cholinergic Terminals in the Cerebral Cortex and Hippocampus in Transgenic Mice Carrying Mutated Presenilin-1 and Amyloid Precursor Protein Transgenes , 1999, The Journal of Neuroscience.

[56]  T. Town,et al.  Soluble β-amyloid peptides mediate vasoactivity via activation of a pro-inflammatory pathway , 2000, Neurobiology of Aging.

[57]  D. Price,et al.  Mutant genes in familial Alzheimer's disease and transgenic models. , 1998, Annual review of neuroscience.

[58]  D. Price,et al.  Localization of superoxide dismutases in Alzheimer's disease and Down's syndrome neocortex and hippocampus. , 1995, The American journal of pathology.

[59]  S. Tanada,et al.  Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: A positron emission tomography study , 2000, Annals of neurology.

[60]  Gary Lynch,et al.  Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice , 1999, Brain Research.

[61]  M. Nieto,et al.  Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice , 2004, Neuroscience.

[62]  S. Greenberg.  Cerebral amyloid angiopathy and dementia: two amyloids are worse than one. , 2002, Neurology.

[63]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[64]  E. Matsubara,et al.  Impaired neurotransmitter systems by Aβ amyloidosis in APPsw transgenic mice overexpressing amyloid β protein precursor , 2000, Neuroscience Letters.

[65]  J. Kašparová,et al.  β-Amyloid and Cholinergic Neurons , 2003, Neurochemical Research.

[66]  X. Tong,et al.  Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease , 1999, Neuroscience.

[67]  T. Arendt,et al.  Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice. , 2003, Brain research.

[68]  C. Iadecola,et al.  Aβ-Induced Vascular Oxidative Stress and Attenuation of Functional Hyperemia in Mouse Somatosensory Cortex , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[69]  B. K. Hartman,et al.  Ultrastructural and morphometric features of the acetylcholine innervation in adult rat parietal cortex: An electron microscopic study in serial sections , 1994, The Journal of comparative neurology.

[70]  W. Ma,et al.  Amyloid β peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures , 2002, Neuroscience.

[71]  J. Hardy,et al.  Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP , 2001, Science.

[72]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[73]  X. Tong,et al.  Basal forebrain nitric oxide synthase (NOS)‐containing neurons project to microvessels and NOS neurons in the rat neocortex: cellular basis for cortical blood flow regulation , 2000, The European journal of neuroscience.

[74]  E. Mufson,et al.  Neuropathology of Mice Carrying Mutant APPswe and/or PS1M146L Transgenes: Alterations in the p75NTR Cholinergic Basal Forebrain Septohippocampal Pathway , 2001, Experimental Neurology.

[75]  Mikio Shoji,et al.  Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease , 2001, The Journal of Neuroscience.

[76]  J. Coyle,et al.  Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. , 1982, Science.

[77]  D. German,et al.  Cholinergic neuropathology in a mouse model of Alzheimer's disease , 2003, The Journal of comparative neurology.

[78]  T. Beach,et al.  The Cholinergic Deficit Coincides with Aβ Deposition at the Earliest Histopathologic Stages of Alzheimer Disease , 2000, Journal of neuropathology and experimental neurology.

[79]  M. Tabaton,et al.  Amyloid‐β Deposition in Alzheimer Transgenic Mice Is Associated with Oxidative Stress , 1998, Journal of neurochemistry.

[80]  P. Davies,et al.  SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE , 1976, The Lancet.

[81]  P. A. Peterson,et al.  beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. , 2000, The Journal of biological chemistry.

[82]  E. McGowan,et al.  Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes , 2001, Neuroreport.

[83]  C. Geula,et al.  Special properties of cholinesterases in the cerebral cortex of Alzheimer's disease , 1989, Brain Research.

[84]  M. Mattson,et al.  Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF , 1993, Brain Research.

[85]  Jacob Raber,et al.  Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[86]  B. Yankner.  Mechanisms of Neuronal Degeneration in Alzheimer's Disease , 1996, Neuron.

[87]  D. Moechars,et al.  Acetylcholinesterase-Positive Fiber Deafferentation and Cell Shrinkage in the Septohippocampal Pathway of Aged Amyloid Precursor Protein London Mutant Transgenic Mice , 2000, Neurobiology of Disease.

[88]  M. Key,et al.  Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. , 1991, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[89]  L. Descarries,et al.  Cholinergic innervation in adult rat cerebral cortex: A quantitative immunocytochemical description , 2000, The Journal of comparative neurology.

[90]  J. Kemp,et al.  Inhibition of the electrostatic interaction between beta-amyloid peptide and membranes prevents beta-amyloid-induced toxicity. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[91]  R. Quirion,et al.  Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies , 2002, Progress in Neurobiology.