"Expanding our structural and functional comprehension of the molecules involved in neurodegenerative diseases is crucial in the development of innovative therapy. Basic biomedical research provides pivotal advances to our knowledge about Alzheimer disease (AD), a progressive yet incurable brain disorder. My work focuses on the sheddase beta-secretase (BACE1), which catalyzes the first step in the production of amyloid beta (Abeta), the core component found in the pathological plaques of AD brains. BACE1 depletion abolishes Abeta production and consequently, BACE1 inhibitors that are currently in clinical trials build hope to attenuate amyloid production. However, the canonical enzymatic function of BACE1 is implicated in diverse physiological processes in the nervous system, such as myelination and axon guidance. Overall, the regulation and "sheddase" function of BACE1 is linked to multiple substrates and a variety of important cellular processes in health and disease. New links between BACE1 and copper homeostasis have emerged, based on reports that BACE1 and its substrate Amyloid Precursor Protein (APP) bind copper ions. Copper is an essential bioactive trace metal and altered copper homeostasis has been implicated in both physiological and pathophysiological aging. Recently, we characterized a highly conserved amino acid motif that spans the entire transmembrane sequence (TMS) of BACE1. We discovered that this motif, reminiscent of a high affinity binding site for Cu(I) of copper-transporting proteins, can bind copper ions. The data here highlight that full-length cellular BACE1 exists as trimers, which creates a potential binding pocket for Cu(I) in the TMS. Furthermore, we show the overall importance of the TMS in regulating copper homeostasis. Therefore, therapeutic strategies aimed at decreasing BACE1 protein levels should be regarded with caution, since adverse effects in copper homeostasis may occur. In AD, an important feature of BACE1 is its canonical pro-amyloidogenic cleavage at the beta-site within APP, which leads to Abeta production. However, BACE1 can also cleave within the Abeta sequence at putative anti-amyloidogenic sites. With the help of newly developed assays, we show that BACE1 has a novel vital role in amyloid degradation. Furthermore, the detection of amyloidolytic fragments in AD affected brains imply that the enzymatic Abeta degradation is deregulated in the pathogenesis. Since biochemical changes in AD may precede the onset of cognitive symptoms, we focused our attention on the quantification of amyloidolytic cleavage products in the cerebrospinal fluid (CSF) of individuals with mild cognitive impairment (MCI) and those without symptoms having an increased risk of AD dementia. We found that Abeta34, an amyloidolytic fragment, was elevated in MCI patients, who later converted to AD dementia. Therefore, Abeta34 may be useful as an early diagnostic indicator. Furthermore, we found that Abeta34 correlated with CSF levels of tau, a marker of neurodegeneration. Given BACE1's essential involvement in the generation of Abeta34 in vitro, these results imply that BACE1 activity correlates with neurodegeneration. Ultimately, CSF levels of Abeta34 could be informative on BACE1 activity in the human brain and potentially provide physicians with an estimate of the optimal therapeutic time window for the administration of safe BACE1 inhibitors to prevent AD." --