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The Journal of Neuroscience, January 15, 2002, 22(2):515-522
Amyloid-Associated Neuron Loss and Gliogenesis in the Neocortex
of Amyloid Precursor Protein Transgenic Mice
Luca
Bondolfi1,
Michael
Calhoun1,
Florian
Ermini1,
H. Georg
Kuhn2,
Karl-Heinz
Wiederhold3,
Lary
Walker4,
Matthias
Staufenbiel3, and
Mathias
Jucker1
1 Department of Neuropathology, Institute of Pathology,
University of Basel, CH-4003 Basel, Switzerland,
2 Department of Neurology, University of Regensburg,
D-93053 Regensburg, Germany, 3 Novartis Pharma AG, Nervous
System Research, CH-4002 Basel, Switzerland, and
4 CNS Pharmacology, Pfizer Ann Arbor Laboratories, Ann
Arbor, Michigan 48105
APP23 transgenic mice express mutant human amyloid precursor
protein and develop amyloid plaques predominantly in neocortex and
hippocampus progressively with age, similar to Alzheimer's disease. We
have previously reported neuron loss in the hippocampal CA1 region of
14- to 18-month-old APP23 mice. In contrast, no neuron loss was found
in neocortex. In the present study we have reinvestigated neocortical
neuron numbers in adult and aged APP23 mice. Surprisingly, results
revealed that 8-month-old APP23 mice have 13 and 14% more neocortical
neurons compared with 8-month-old wild-type and 27-month-old APP23
mice, respectively. In 27-month-old APP23 mice we found an inverse
correlation between amyloid load and neuron number. These results
suggest that APP23 mice have more neurons until they develop amyloid
plaques but then lose neurons in the process of cerebral
amyloidogenesis. Supporting this notion, we found more neurons with a
necrotic-apoptotic phenotype in the neocortex of 24-month-old APP23
mice compared with age-matched wild-type mice. Stimulated by recent
reports that demonstrated neurogenesis after targeted neuron death in
the mouse neocortex, we have also examined neurogenesis in APP23 mice.
Strikingly, we found a fourfold to sixfold increase in newly produced
cells in 24-month-old APP23 mice compared with both age-matched
wild-type mice and young APP23 transgenic mice. However, subsequent
cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were microglial and to
a lesser extent astroglial cells. We conclude that cerebral amyloidosis
in APP23 mice causes a modest neuron loss in neocortex and induces
marked gliogenesis.
Key words:
Alzheimer's disease; amyloid; APP; A ; CNS; brain; transgenic mouse; stereology; neurodegeneration; stem cells; neurogenesis; gliogenesis; microglia; aging
Copyright © 2002 Society for Neuroscience 0270-6474/02/222515-08$05.00/0
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