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APP^sub sw^ Transgenic Mice Develop Age-related AP Deposits and Neuropil Abnormalities, but no Neuronal Loss in CA1
Abstract. The recent availability of transgenic mouse models of Alzheimer disease has allowed direct in vivo assessment of the molecular and neuropathological effects of cerebral amyloid deposition. We examined 16-month-old Tg(HuAPP695. K670N-M671L)2576 mice expressing human APP K670N-M671L (APP^sub sw^), which have amyloid deposition and behavioral deficits by 11 months of age. Transgene expression is predominantly neuronal, and results in amyloid deposits, comparable to human senile plaques, at terminal zones of transgene positive neurons in cortical and limbic regions. Amyloid deposits were associated with prominent gliosis and neuritic dystrophy, without neuronal loss in CAl, loss of synaptophysin immunoreactivity in the hippocampal dentate gyrus, or loss of messenger RNA for neuronal synaptic, cytoskeletal, or metabolic proteins. We conclude that AP is not acutely neurotoxic, but can disrupt neuronal processes and provoke an inflammatory response.
Key Words: Alzheimer disease; Amyloid beta protein; Amyloid precursor protein; Hippocampus; mRNA; Synaptophysin; Transgenic models.
INTRODUCTION
The "amyloid hypothesis" of Alzheimer disease (AD) asserts that amyloid beta protein (AP) induces neuronal loss with resultant cognitive impairment (1). Although AP neurotoxicity has been demonstrated in vitro (2-6), confirming AP neurotoxicity in vivo has been more problematic (7-9). Moreover, the amount of AP deposited in AD brain does not correlate with the degree of clinical symptoms (10-12) or the amount of neuronal loss (13, 14).
The development of a transgenic mouse that exhibits age-related AP deposition and behavioral impairment (15) allows us to test the hypothesis that AP deposits are directly neurotoxic in vivo. The Tg(HuAPP695.K670NM671L)2576 transgenic mouse (Tg2576) contains the 695 amino acid splice form of the human amyloid precursor protein, hAPP695, modified by the Swedish familial AD double mutation K670N-M671L, driven by the hamster prion protein promoter. The transgene is expressed in C57B6/SJL F1 mice backcrossed to C57B6 breeders at levels 5 times that of endogenous mouse APP; AP deposition occurs by 11 to 13 months of age, and behavioral deficits in Y-maze and water-maze are evident by 10 months of age in transgene-positive offspring of the founder (15). We investigated regional transgene expression, amyloid deposition, neuronal mRNA expression, plaque morphology, synaptophysin immunoreactivity and neuronal counts in 16-month-old Tg2576 transgenic mice and nontransgenic...