Developing a Model for Slow Hypoxic Injury and Vascular Degeneration in Amyloid Burdened Brains

Abstract

The breakdown of neurovascular systems may play a crucial role in the pathogenesis of Alzheimer's disease. However whether this breakdown initiates a degenerative mechanism or is the consequence of some other deleterious process remains unknown. We examined hippocampal pathology in double transgenic mice overexpressing a human mutant gene encoding the amyloid precursor protein (APPSwe/Ind) using a combination of histochemistry and stereologic techniques. Expression of APPSwe/Ind in these mice is driven by a tetracycline-sensitive promoter. Tetracycline transcriptional activator (tTA), the second transgene, is driven in turn by a CAM KIIa promoter that is only active in neurons. Thus this double transgenic construct allows us to control expression of APPSwe/Ind with doxycycline. Utilizing this characteristic, we created three distinct experimental groups: A, display abeta plaque pathology and express APPSwe/Ind at time of sacrifice; B, display abeta plaque pathology but do not express APPSwe/Ind at time of sacrifice; and C, do not display abeta plaque pathology but do express APPSwe/Ind at time of sacrifice. Stereologic investigation revealed decreased hippocampal volume in groups A(n=5) and B(n=5) when compared to group C(n=5) and age-matched wildtype (n=9).

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