The effects of secreted amyloid precursor protein-alpha on cell proliferation in adult rat dentate gyrus

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes severe memory and cognitive decline and currently affects millions of people worldwide. Abnormal cleavage of the amyloid precursor protein (APP) has been linked to AD because of the important role APP has in neural plasticity. When APP is cleaved by β-secretase and γ-secretase rather than α-secretase, it can result in the amyloid-β toxicity seen in AD. This abnormal chain of events is also linked to learning and memory deficits, primarily in the dentate gyrus (DG) of the hippocampus. The DG is essential for short-term memory processing and plasticity. Additionally, the subgranular zone (SGZ) of the DG is just one of two areas in the brain where neurogenesis continues into adulthood. Neurogenesis is not only imperative for healthy brain functioning, but also displays neuroprotective qualities and may assist neurological repair. Therefore, neurogenesis in the DG could improve or even restore learning and memory deficits seen in neurodegenerative disorders such as AD. APP cleavage is such a crucial factor because just as APP produces a neurotoxic fragment when cleaved by β- and γ-secretases, it also produces a neuroprotective fragment when cleaved by α-secretase. This fragment is known as secreted amyloid precursor protein-α, or sAPPα. sAPPα has been shown to assist in brain repair, promote neural proliferation in the subventricular zone (SVZ), and regulate neuronal function. Accordingly, sAPPα may be able to promote neurogenesis in the SGZ, thus improving learning and memory in the DG. Here, we investigate the effects of sAPPα on SGZ proliferation by infusing sAPPα into the healthy adult rat DG through the use of cannulae and Alzet osmotic mini-pumps. These mini-pumps allow infusion of specific volumes at pre-determined rates. Rats receiving a sAPPα pump in one hemisphere received a vehicle pump in the other hemisphere. Control rats received only a vehicle pump in one hemisphere. After 7 days, rats were injected with bromodeoxyuridine (BrdU) and sacrificed via intracardial perfusion. Eight brain sections near cannula insertion were chosen for staining from each animal and were organized from anterior to posterior. BrdU-labelled cells in the SGZ and granule cell layer were quantified and results analyzed through analysis of variance tests. Comparisons between groups, hemispheres, sections, and ages of animals were made, with no significant differences being found in any of the comparisons. There are several ways in which these results can be interpreted. As an unexpectedly low number of cells were discovered in many sections, there may be an issue with the BrdU concentration. Alternatively, the solutions in the pumps or even the pumps themselves could be influencing the cell proliferation unilaterally or potentially even bilaterally. Another possibility is that sAPPα is simply not inducing cell proliferation in the healthy adult DG. Whichever one or more of these explanations are correct, the results from this study indicate many directions for future research that will help uncover the true impact of sAPPα not only on cell proliferation, but also on neurogenesis in the DG and memory-related behavior.