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RESEARCH PRODUCT

Mice are not Men: ADAM30 Findings Emphasize a Broader Look Towards Murine Alzheimer's Disease Models

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Due to the growing population of people at advanced age, the number of patients affected by Alzheimer's disease (AD) is increasing tremendously. In 2015 about 46.8 million people suffered from AD worldwide which is estimated to increase to 131.5 million by 2050. Brains of AD patients all show a common histopathology; they are marked by an atrophy and degeneration that is caused by a severe loss of neurons and synapses (Braak and Del Tredici, 2012). Moreover, so-called extracellular senile plaques that consist of predominantly amyloid β (Aβ) peptides can be detected in the grey matter where they surround neurons. Since generation of Aβ peptides is hypothesized to play a major role in AD pathogenesis, it is essential to decipher the enzymatic cascade leading to the generation of Aβ. Most of the Aβ-peptides are initially generated by β-secretase (BACE1) with subsequent γ-secretase cleavage of the amyloid precursor protein (APP). In contrast, ADAM10 as α-secretase cleaves APP within the Aβ sequence and prevents the generation and subsequent accumulation of this neurotoxic peptide. Recently, several studies described the presence of N-terminally truncated Aβ peptides in brain or cerebrospinal fluid (CSF), including Aβ2–42, pyroglutamate Aβ3–42 (AβpE3–42) or Aβ4–42 (Kummer and Heneka, 2014). However, BACE-1 is incapable in generating these truncated peptides, since it only cleaves APP in amino acid positions p1 or p11 of the Aβ peptide (Vassar et al., 1999). Therefore, it is of utmost importance to identify new players in APP metabolism that might have been overlooked so far, possibly due to low expression, lack of appropriate tools, or other experimental confounds.