Abstract:
Alzheimer’s disease (AD) is the leading form of dementia affecting approximately 35 million people worldwide. So far, only symptomatic treatment is approved which does not change the course of the disease. Over the last years, prevention trials for AD started to rise new hope for effective therapies based on the knowledge that changes in amyloid-β (Aβ) levels can be detected more than two decades before symptom onset. However, the most beneficial timepoint for early intervention and the best treatment strategies remain unknown. We examined the concepts of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition and anti Aβ immunization as prevention strategies. In the first study of this thesis, the optimal timepoint for intervention during pathogenesis was determined. Amyloid precursor protein (APP) transgenic mice were treated for three months with a potent BACE1 inhibitor at an early, intermediate or late stage of pathology or chronically for either half-lifelong or lifelong duration. Effects on neurodegeneration and associated pathologies were established. In the second study, well described anti-Aβ antibodies were applied to APP transgenic mice at initial stage of β-amyloidosis. Their ability to neutralize seeding-active Aβ assemblies was investigated in order to assess preventive effects at sub-threshold Aβ levels before Aβ increase can be detected. Furthermore, antibody recognition profiles using size-fractionated brain-derived Aβ assemblies were established. In the first study, early BACE1 inhibition robustly reduced Aβ deposition and halted neurodegeneration, whereas at later stages of pathology, neurodegeneration became uncoupled of β-amyloidosis. In the second study, acute immunization with an anti-Aβ antibody led to a long-term significant reduction of Aβ deposition and downstream pathologies, demonstrating the presence of pathogenic Aβ seeds before Aβ deposition can be detected. Findings imply that preclinical therapy should shift to initial stages of Aβ dyshomeostasis before β-amyloid deposition is detectable. This primary prevention approach may forestall further seed formation and neurodegeneration, thereby preventing the onset of AD.
Alzheimer's disease