Oncogenic Parallels in Alzheimer Disease

Alzheimer disease (AD), the leading cause of senile dementia, is characterized by the selective degeneration of specific neuronal populations responsible for memory acquisition and storage. While a multitude of mechanisms have been proposed to account for such neuronal vulnerability, in this body of work we have focused on three crucial elements; two of which are amongst the earliest and most pervasive changes in the disease, namely alterations in oxidative stress and cell cycle, and one of which is central to the disease process, namely cell death. In Chapter 2, we demonstrate that NADPH quinine oxidoreductase 1 (NQO1) and bleomicine hydrolase, sensitive redox sensors, are upregulated in those neurons vulnerable to degeneration indicating that oxidative stress is a key and early determinant of disease. In Chapter 3, we focus on cell cycle alterations using a specific marker (Mrg 15) of cellular emergence from senescence, as well as downstream markers of a successful passage through the cell cycle, namely p27 and CIP-1-associated regulator of Cyclin B (CARB). Our data not only further the evidence for a role of mitotic dysfunction in AD but also suggest that neurons exit from their normal senscent status and at least progress to the G2/M phase of cellular division. In Chapter 4, we demonstrate that, while initiation of apoptosis is an invariant feature of neurons in the brains of individual with AD, there was no evidence of later apoptotic features such as the activation of effector caspases. This novel phenomenon, we termed “Abortosis”. Since alterations in redox balance, cell cycle control and avoidance of apoptosis are also key to successful oncogenic transformation, in Chapter 5, we investigated parallels between oncogenesis and AD. Specifically, we determined a key role in AD for two canonical cancer-related proteins, BRCA-1 and retinoblastoma protein, and also found evidence for alterations in the cancer-related matrix metaloproteases, ADAMs 1 and 2. All of these parallels between AD and neoplasia indicate that AD could represent a cancer in the postmitotic environment and show how the postmitotic state behaves given oncogenic stimulation. Elucidation of mechanisms of this oncogenic stimulation will have broad applications beyond AD itself.