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The Journal of Neuroscience, April 15, 2002, 22(8):3234-3243
Cholinergic Changes in the APP23 Transgenic Mouse Model of
Cerebral Amyloidosis
Sonia
Boncristiano1, *,
Michael E.
Calhoun1, *,
Peter
H.
Kelly2,
Michelle
Pfeifer1,
Luca
Bondolfi1,
Martina
Stalder1,
Amie L.
Phinney1,
Dorothee
Abramowski2,
Christine
Sturchler-Pierrat2,
Albert
Enz2,
Bernd
Sommer2,
Matthias
Staufenbiel2, and
Mathias
Jucker1
1 Neuropathology, Institute for Pathology, University
of Basel, CH-4003 Basel, Switzerland, and 2 Novartis Pharma
AG, Nervous System Research, CH-4002 Basel, Switzerland
Alzheimer's Disease (AD) is a neurodegenerative disorder that is
characterized by extracellular deposits of amyloid- peptide (A)
and a severe depletion of the cholinergic system, although the
relationship between these two events is poorly understood. In the
neocortex, there is a loss of cholinergic fibers and receptors and a
decrease of both choline acetyltransferase (ChAT) and
acetylcholinesterase enzyme activities. The nucleus basalis of
Meynert (NBM), which provides the major cholinergic input to the
neocortex, undergoes profound neuron loss in AD. In the present study,
we have examined the cholinergic alterations in amyloid precursor
protein transgenic mice (APP23), a mouse model of cerebral
-amyloidosis. In aged APP23 mice, our results reveal modest
decreases in cortical cholinergic enzyme activity compared with
age-matched wild-type mice. Total cholinergic fiber length was more
severely affected, with 29 and 35% decreases in the neocortex of aged
APP23 mice compared with age-matched wild-type mice and young
transgenic mice, respectively. However, there was no loss of
cholinergic basal forebrain neurons in these aged APP23 mice,
suggesting that the cortical cholinergic deficit in APP23 mice is
locally induced by the deposition of amyloid and is not caused by a
loss of cholinergic basal forebrain neurons. To study the impact of
cholinergic basal forebrain degeneration on cortical amyloid
deposition, we performed unilateral NBM lesions in adult APP23 mice.
Three to 8 months after lesioning, a 38% reduction in ChAT activity
and significant cholinergic fiber loss were observed in the ipsilateral
frontal cortex. There was a 19% decrease in A levels of the
ipsilateral compared with contralateral frontal cortex with no change
in the ratio of A40 to A42. We conclude that the severe
cholinergic deficit in AD is caused by both the loss of cholinergic
basal forebrain neurons and locally by cerebral amyloidosis in the
neocortex. Moreover, our results suggest that disruption of the basal
cholinergic forebrain system does not promote cerebral amyloidosis in
APP23 transgenic mice.
Key words:
Alzheimer's disease; APP; amyloid; basal forebrain; cholinergic system; ChAT; AChE; neurodegeneration; nucleus basalis of
Meynert; neocortex; lesion; mouse; stereology; hippocampus; aging
*
S.B. and M.E.C. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/2283234-10$05.00/0
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