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Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein.

Oster-Granite, Mary Lou, McPhie, Donna L., Greenan, Jane, Neve, Rachael L.·1996·The Journal of Neuroscience
DOI 10.1523/jneurosci.16-21-06732.1996
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Abstract

The molecular basis for the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature in Alzheimer’s disease (AD) is incompletely understood. We have proposed that one molecule common to these abnormal processes is a fragment of the Alzheimer amyloid precursor protein (APP) comprising the C-terminal 100 amino acids of this molecule (APP-C100). We tested this hypothesis by creating transgenic mice expressing APP-C100 in the brain. We report here that aging (18–28 month) APP-C100 transgenic mice exhibit profound degeneration of neurons and synapses in Ammon’s horn and the dentate gyrus of the hippocampal formation. Of the 106 transgenic mice between 8 and 28 months of age that were examined, all of those older than 18 months displayed severe hippocampal degeneration. The numerous degenerating axonal profiles contained increased numbers of neurofilaments, whorls of membrane, and accumulations of debris resembling secondary lysosomes near the cell body. The dendrites of degenerating granule and pyramidal cells contained disorganized, wavy microtubules. Cerebral blood vessels had thickened refractile basal laminae, and microglia laden with debris lay adjacent to larger venous vessels. Mice transgenic for Flag-APP-C100 (in which the hydrophilic Flag tag was fused to the N terminus of APP-C100) showed a similar degree of neurodegeneration in the hippocampal formation as early as 12 months of age. The 45 control mice displayed only occasional necrotic cells and no extensive cell degeneration in the same brain regions. These findings show that APP-C100 is capable of causing some of the neuropathological features of AD.

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Crossref · 10.1523/jneurosci.16-21-06732.1996

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Figures

Figure 1 A , Granule cell layer of a transgene-positive 23-month-old male progeny from two F1 heterozygous APP-C100 line-seven mice. The sections are stained with toluidine blue. Note the numerous degenerating neurons in the cell layer (some indicated with white arrowheads ) and in the neuropil below. Some dystrophic dendrites are evident (2800 3 magnification). B , Pyramidal cell layer of 28-month-old heterozygous male APPC100 line-seven founder mouse. Note the numerous degenerating neurons in the pyramidal layer ( white arrowheads ). Degenerating dystrophic dendrites are also evident ( arrows ) (2800 3 magnification).
Figure 1 A , Granule cell layer of a transgene-positive 23-month-old male progeny from two F1 heterozygous APP-C100 line-seven mice. The sections are stained with toluidine blue. Note the numerous degenerating neurons in the cell layer (some indicated with white arrowheads ) and in the neuropil below. Some dystrophic dendrites are evident (2800 3 magnification). B , Pyramidal cell layer of 28-month-old heterozygous male APPC100 line-seven founder mouse. Note the numerous degenerating neurons in the pyramidal layer ( white arrowheads ). Degenerating dystrophic dendrites are also evident ( arrows ) (2800 3 magnification).CC-BY-NC-SA · From the PDF
Image 2
CC-BY-NC-SA · From the PDF
Figure 2 A , Pyramidal cell layer of male 14.5-month-old Flag-APP-C100 line-one founder mouse. Observe the reduced cell density and the numerous dystrophic dendrites and degenerating neurons in the pyramidal cell layer ( white arrowheads ) (2800 3 magnification). B , Pyramidal cell layer of 14.5-month-old male Flag-APP-C100 line-17 founder mouse. Observe the degenerating neurons in the pyramidal cell layer and underlying neuropil. Degenerating dystrophic dendrites are also evident ( arrows ) (2800 3 magnification).
Figure 2 A , Pyramidal cell layer of male 14.5-month-old Flag-APP-C100 line-one founder mouse. Observe the reduced cell density and the numerous dystrophic dendrites and degenerating neurons in the pyramidal cell layer ( white arrowheads ) (2800 3 magnification). B , Pyramidal cell layer of 14.5-month-old male Flag-APP-C100 line-17 founder mouse. Observe the degenerating neurons in the pyramidal cell layer and underlying neuropil. Degenerating dystrophic dendrites are also evident ( arrows ) (2800 3 magnification).CC-BY-NC-SA · From the PDF
Figure 4 A , Neuropil of hippocampal formation of 24-month-old SJL/J male mouse. Note that the neurons are well spaced and few occur as duets with cells that appear to be glial in origin, such as those shown by the black arrows (2800 3 magnification). B , Neuropil of hippocampal formation of 24-month-old female APP-C100 line-seven F1 mouse. Two degenerating neurons and one healthy neuron make up this field. Observe the cytoplasmic accumulations of dense granular material that represent the aberrant secondary lysosomes that accumulate in these neurons as the mice age ( black arrows ). Cells adjacent to the neurons appear to have many characteristics of glial or microglial cells ( star ) (7000 3 magnification). C , Neuropil of hippocampal formation of 24-month-old female APP-C100 line-seven F1 mouse. Note the glial cells in apposition to degenerating and healthy neurons ( star ) and the dense cells ( star ) that lie close to blood vessels and resemble pericytes. Ultrastructural examination of these cells reveals that they contain degenerating debris and have a characteristic nuclear morphology that suggests they are microglial cells. Black arrows indicate the secondary lysosomal accumulations evident in the two neurons (7000 3 magnification).
Figure 4 A , Neuropil of hippocampal formation of 24-month-old SJL/J male mouse. Note that the neurons are well spaced and few occur as duets with cells that appear to be glial in origin, such as those shown by the black arrows (2800 3 magnification). B , Neuropil of hippocampal formation of 24-month-old female APP-C100 line-seven F1 mouse. Two degenerating neurons and one healthy neuron make up this field. Observe the cytoplasmic accumulations of dense granular material that represent the aberrant secondary lysosomes that accumulate in these neurons as the mice age ( black arrows ). Cells adjacent to the neurons appear to have many characteristics of glial or microglial cells ( star ) (7000 3 magnification). C , Neuropil of hippocampal formation of 24-month-old female APP-C100 line-seven F1 mouse. Note the glial cells in apposition to degenerating and healthy neurons ( star ) and the dense cells ( star ) that lie close to blood vessels and resemble pericytes. Ultrastructural examination of these cells reveals that they contain degenerating debris and have a characteristic nuclear morphology that suggests they are microglial cells. Black arrows indicate the secondary lysosomal accumulations evident in the two neurons (7000 3 magnification).CC-BY-NC-SA · From the PDF
Image 5
CC-BY-NC-SA · From the PDF
Figure 6 A , Degenerating synapses in neuropil of 28-month-old male APP-C100 line-seven F1 mouse. Note the degenerating dendritic process in this synaptic complex ( star ). Also, observe whorls of membrane in cell processes, both axonal and dendritic ( white arrows ), and axons that contain large numbers of neurofilaments ( A ) (15,000 3 magnification). B , Degenerating neuropil from another region of the hippocampal formation of the same 28-month-old male APP-C100 line-seven F1 mouse. Again, axons with reasonable amounts of myelin contain densely packed neurofilaments ( A ), whorls of membrane ( white arrows ) are seen in dendrites ( open black arrows ), and a synapse in which both axonal and dendritic processes appear to be degenerating is present ( star ) (15,000 3 magnification). C , Neuropil of the underlying dentate gyrus of the hippocampal formation of the same 28-month-old male APP-C100 line-seven F1 mouse. The dentate granule cell for which the nucleus lies adjacent to the capillary contains unusual whorls of membranous material ( black arrow ). The densely heterochromatic nucleus with large active nucleolus that has dense cytoplasm and lies adjacent to the blood vessel as well is interpreted to be a microglial cell ( M ). Observe that the basement membrane of the capillary ( small black arrows ) is thickened and that a cell process laden with debris ( black arrowhead ) lies within the thickened basement membrane.
Figure 6 A , Degenerating synapses in neuropil of 28-month-old male APP-C100 line-seven F1 mouse. Note the degenerating dendritic process in this synaptic complex ( star ). Also, observe whorls of membrane in cell processes, both axonal and dendritic ( white arrows ), and axons that contain large numbers of neurofilaments ( A ) (15,000 3 magnification). B , Degenerating neuropil from another region of the hippocampal formation of the same 28-month-old male APP-C100 line-seven F1 mouse. Again, axons with reasonable amounts of myelin contain densely packed neurofilaments ( A ), whorls of membrane ( white arrows ) are seen in dendrites ( open black arrows ), and a synapse in which both axonal and dendritic processes appear to be degenerating is present ( star ) (15,000 3 magnification). C , Neuropil of the underlying dentate gyrus of the hippocampal formation of the same 28-month-old male APP-C100 line-seven F1 mouse. The dentate granule cell for which the nucleus lies adjacent to the capillary contains unusual whorls of membranous material ( black arrow ). The densely heterochromatic nucleus with large active nucleolus that has dense cytoplasm and lies adjacent to the blood vessel as well is interpreted to be a microglial cell ( M ). Observe that the basement membrane of the capillary ( small black arrows ) is thickened and that a cell process laden with debris ( black arrowhead ) lies within the thickened basement membrane.CC-BY-NC-SA · From the PDF

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Metadata

Authors
Oster-Granite, M. L., McPhie, D. L., Greenan, J., & Neve, R. L.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
1996-11-01
Volume
16
Issue
21
Pages
6732-6741
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.16-21-06732.1996
Cited by
162
References
4
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 181 d)

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