APP Knockout Mice Experience Acute Mortality as the Result of Ischemia

Maya A Koike,Kim N Green,Bernard Choi,Elaine Nguyen,Rombod Rahimian,Bruce J Tromberg,Frank M Laferla,Jonathan Pham,James J Yeh,Alexander J Lin,Simone Di Giovanni

doi:10.1371/journal.pone.0042665

Maya A Koike, Kim N Green + Show 9 more

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https://doi.org/10.1371/journal.pone.0042665

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Abstract

The incidence of Alzheimer’s disease increases in people who have had an ischemic episode. Furthermore, APP expression is increased following ischemic or hypoxic conditions, as is the production of the Aβ peptide. To address the question of why APP and Aβ are increased in hypoxic and ischemic conditions we induced an ischemic episode in APP knockout mice (APP−/−) and BACE1 knockout mice (BACE−/−). We find that both APP−/− and BACE−/− mice have a dramatically increased risk of mortality as a result of cerebral ischemia. Furthermore, APP knockout mice have reduced cerebral blood flow in response to hypoxia, while wild-type mice maintain or increase cerebral blood flow to the same conditions. The transcription factor, serum response factor (SRF), and calcium-binding molecule, calsequestrin, both involved in vascular regulation, are significantly altered in the brains of APP−/− mice compared to wild type controls. These results show that APP regulates cerebral blood flow in response to hypoxia, and that it, and its cleavage fragments, are crucial for rapid adaptation to ischemic conditions.

Highlights

Alzheimer’s disease is a progressive neurodegenerative disease that affects the elderly
We examined the brains of the mice to determine if the mortality we observed in the APP2/2 and BACE2/2 mice resulted from a gross increase in cell loss following ischemia
We found that the APP2/2 mice and BACE2/2 mice suffered from acute mortality during and after the occlusion period, which was not seen in the wild type control animals

Summary

Introduction

Alzheimer’s disease is a progressive neurodegenerative disease that affects the elderly. The disease is thought to occur due to the accumulation of the Ab peptide in the aging brain. The accumulation of Ab in soluble oligomers and extracellular plaques initiates a cascade of downstream events, culminating in synaptic and neuronal toxicity [1]. This loss of synapses and neurons likely causes the memory loss and cognitive decline associated with the disease [2]. The majority of disease modifying therapeutics are aimed squarely at inhibiting the cleavage of APP by its respective proteases, little is known about the endogenous function of APP and what consequences modulating its cleavage and expression will have in the aged brain

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