Cerebral Amyloid Induces Aberrant Axonal Sprouting and Ectopic Terminal Formation in Amyloid Precursor Protein Transgenic Mice

A characteristic feature of Alzheimer’s disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.

[1]  J Carter,et al.  Molecular Pathology of Alzheimer's Disease , 2013 .

[2]  B. Sommer,et al.  Association of microglia with amyloid plaques in brains of APP23 transgenic mice. , 1999, The American journal of pathology.

[3]  H. Lipp,et al.  No hippocampal neuron or synaptic bouton loss in learning-impaired aged β-Amyloid precursor protein-null mice , 1999, Neuroscience.

[4]  M. Rafii,et al.  Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Frotscher,et al.  Different Primary Target Cells Are Important for Fiber Lamination in the Fascia Dentata: A Lesson from Reeler Mutant Mice , 1999, Experimental Neurology.

[6]  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.

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

[8]  B. Hyman,et al.  Abeta associated neuropil changes: correlation with neuronal loss and dementia. , 1998, Journal of neuropathology and experimental neurology.

[9]  B. Sommer,et al.  Neuron loss in APP transgenic mice , 1998, Nature.

[10]  M. Hasselmo,et al.  The hippocampus as an associator of discontiguous events , 1998, Trends in Neurosciences.

[11]  Changiz Geula,et al.  Abnormalities of neural circuitry in Alzheimer's disease , 1998, Neurology.

[12]  F. Westermann,et al.  Serum Leptin Is Suppressed by Growth Hormone Therapy in Growth Hormone-Deficient Children , 1998, Hormone Research in Paediatrics.

[13]  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.

[14]  P. Greengard,et al.  Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Frotscher,et al.  Sprouting in the hippocampus is layer-specific , 1997, Trends in Neurosciences.

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

[17]  M. Frotscher,et al.  A Novel Entorhinal Projection to the Rat Dentate Gyrus: Direct Innervation of Proximal Dendrites and Cell Bodies of Granule Cells and GABAergic Neurons , 1996, The Journal of Neuroscience.

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

[19]  J. Kapfhammer,et al.  Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice , 1995, Cell.

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

[21]  D. Ingram,et al.  Age-related deposition of glia-associated fibrillar material in brains of c57BL/6 mice , 1994, Neuroscience.

[22]  D. Selkoe,et al.  Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[23]  H. Chui,et al.  Association between vascular basement membrane components and the lesions of Alzheimer's disease , 1991, Journal of neuroscience research.

[24]  Michael Alford,et al.  Patterns of aberrant sprouting in alzheimer's disease , 1991, Neuron.

[25]  R. Neve,et al.  The pattern of GAP-43 immunostaining changes in the rat hippocampal formation during reactive synaptogenesis. , 1990, Brain research. Molecular brain research.

[26]  D. Nochlin,et al.  The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. , 1988, The American journal of pathology.

[27]  K. Kosik,et al.  Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer's disease , 1987, Annals of neurology.

[28]  C. Cotman,et al.  Senile plaques as aberrant sprout-stimulating structures , 1986, Experimental Neurology.

[29]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[30]  C. Cotman,et al.  Plasticity of hippocampal circuitry in Alzheimer's disease. , 1985, Science.

[31]  C. Gerfen,et al.  An anterograde neuroanatomical tracing method that shows the detailed morphology of neurons, their axons and terminals: Immunohistochemical localization of an axonally transported plant lectin,Phaseolus vulgaris leucoagglutinin (PHA-L) , 1984, Brain Research.

[32]  O. Steward,et al.  Immunocytochemical localization of actin and microtubule-associated protein MAP2 in dendritic spines. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[33]  W. Cowan,et al.  The organization of certain afferents to the hippocampus and dentate gyrus in normal and reeler mice , 1979, The Journal of comparative neurology.

[34]  A. Ward,et al.  Neuromuscular Diseases of Infancy and Childhood , 1970, Neurology.

[35]  V. Tennyson.  The Fine Structure of the Nervous System. , 1970 .

[36]  A. Nappi,et al.  Alzheimer ' s Disease : Cell-Specific Pathology Isolates the Hippocampal Formation , 2022 .