Abstract:
Alzheimer’s disease (AD) is the leading form of dementia interfering with daily life due to progressive memory loss and cognitive disabilities. With more than 45 million people suffering from dementia worldwide, AD is one of the costliest health conditions to society. Because of an increasing proportion of elderly people the number of individuals living with dementia is expected to more than triple by 2050. Although there are symptomatic treatments available that temporarily slow the worsening of clinical symptoms, a disease-modifying cure is still missing. Therefore, dementia, and AD in particular, is becoming a public health priority evoking worldwide efforts to delay or even prevent the disease from ever developing. The amyloid cascade hypothesis explained in detail in chapter one of this thesis proposes that an impaired homeostasis of production and clearance of the amyloid-β (Aβ) peptide is the trigger initiating a sequence of pathogenic events causing AD. Aβ misfolding and aggregation leads to the accumulation of cerebral amyloid plaques, a typical hallmark of AD. As the pathology progresses, plaques continue to develop and grow, which is suggested to lead to the second disease characteristic, neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau proteins. Aβ as the driving force of this pathological cascade has been regarded as the most reasonable therapeutic target. Therefore the second chapter is dedicated to different therapeutic approaches for AD with particular focus on the β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which is responsible for regulating the production of Aβ. To this end APP transgenic (tg) mice that mimic β-amyloidosis-related features of AD were treated with a potent BACE inhibitor for six months. In response to this long-term therapy, brain Aβ as well as plaque deposition were reduced to levels comparable to six months younger animals. Surprisingly, BACE inhibition also exhibited downstream effects preventing the pathology-dependent increase of tau in the cerebrospinal fluid (CSF). Thus, BACE inhibitors are valuable therapeutic agents and their effectiveness can be predicted by CSF tau measurements in clinical trials. These findings have been published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association (Schelle et al., 2017, Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 13(6), pp.701-709). The third part of this thesis investigated the stability of small Aβ aggregates (Aβ seeds), which share pathogenic properties with the prion protein implicated in transmissible spongiform encephalopathies. Whereas in Aβ seeds inoculated APP tg mice the presence of host-derived Aβ together with the exogenously applied seeds induced their propagation, the injected material was undetectable in App null mice 30 days post inoculation. However, reinoculation with brain extracts from App null mice inoculated with Aβ seeds up to six months harboring Aβ levels below detection, still induced cerebral β-amyloidosis in APP tg hosts. In conclusion, Aβ seeds can persist even in the absence of host Aβ and regain their pathogenic activity as soon as sufficient Aβ becomes available. This discovery indicates on the one hand that lowering Aβ production inhibits the formation of new Aβ seeds and on the other hand that therapeutic intervention is most effective when applied at early stages. These results have been published in Nature Neuroscience (Ye, Fritschi, Schelle et al., 2015, Nature neuroscience, 18(11), pp.1559-61). Recent biomarker studies in familial AD subjects, which revealed that first pathological changes occur up to 25 years before clinical disease onset, supported this idea. Therefore, in the last part, pre-depositing APP tg mice were treated with a combinational therapy based on anti-Aβ immunization to remove Aβ seeds and a BACE inhibitor to block the production of soluble Aβ. Using two different APP tg mouse models results revealed that brain Aβ levels and plaque formation were reduced acutely after the treatment. Moreover, this short but early intervention delayed amyloid pathology after discontinuation of the treatment. Thus, targeting initial Aβ seeds by anti-Aβ combination therapy might be the most promising strategy to effectively prevent cerebral β-amyloidosis. These findings are now prepared for publication (Schelle et al., 2017). In summary, this doctoral thesis highlights the importance of early therapeutic intervention with anti-Aβ drugs in order to prevent AD. Previous studies have shown that treatment of AD patients who have already developed irreversible neurodegeneration might be inadequate to stop the progression of this devastating disorder and could be one reason to explain recent failures of anti-amyloid agents in numerous clinical trials. The results presented in this doctoral thesis indicate that the treatment focus should be shifted toward earlier stages of AD and even toward primary prevention before symptom onset targeting initial Aβ seeds.
