Investigation of BACE1 expression during development and in the context of AD pathology

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and is characterized by progressive and irreversible dementia. Early symptoms include short term memory loss as well as subtle changes in behavior, while in later stages abilities such as language, skilled movement and recognition are affected.

The pathological features of AD are the loss of neurons and the presence of abnormal protein deposits in the brains of patients. These deposits consist either of the tau protein which forms neurofibrillary tangles within neurons or of extracellular aggregates of amyloid β (Aβ) peptides called amyloid plaques.

The latter peptides are thought to initiate a cascade of molecular events (amyloid cascade hypothesis) that eventually lead to the clinical symptoms of AD. The Aβ peptides are generated by the stepwise cleavage of the amyloid precursor protein (APP). In a first rate limiting step, the beta-site APP cleaving enzyme 1 (BACE1) cleaves APP which in a second step is then further cleaved by the γ-secretase resulting in the release of Aβ peptides into the extracellular space. Since it is the key enzyme in the generation of Aβ, BACE1 has been object of intense research and is considered a valuable drug target.

Analysis of brains of AD patients showed increased levels of BACE1 protein/activity which are thought to be responsible for increased Aβ peptide generation. Although there is some evidence that BACE1 may be modulated by Aβ and is strongly expressed especially in the vicinity of amyloid plaques, the cause for (the local) BACE1 up-regulation is unknown.

To gain new insight into the regulation of BACE1, I will address three main questions during my PhD:

1. Does BACE1 protein/activity correlate with the Aβ plaque burden and disease progression? And is the up-regulation of BACE1 a consequence of the increasing plaque and Aβ burden or rather an initial event in AD pathology?
2. Where in the brain and in which cellular context does up-regulation of BACE1 occur?
3. With respect to the very high physiological BACE1 levels observed during development and in the first postnatal week in mice: What are the consequences in regard to production and accumulation of Aβ? And where are cells with high BACE1 levels localized?

In summary, the study of BACE1 regulation in development and AD pathology will contribute to our understanding of the initial events in AD and may be beneficial for the development of new intervention strategies.