The Role of the Anti-Amyloidogenic Secretase ADAM10 in Shedding the APP-like Proteins

Abstract

ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer's disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density. This is due to cleavage of the amyloid precursor protein (APP) within its A-beta stretch and to the release of the extracellular domain of APP with neuroprotective function. Aside from cleaving APP, ADAM10 has been linked to over 40 putative substrates at least in cell culture. These substrates are connected with important cellular functions such as cell migration, stress response and transport. For this contribution we focussed on ADAM10 acting on the APP-like proteins since for some of their representatives - in particular APLP2 and APP-L - a shedding by ADAM10 has been demonstrated in vivo. In addition, the importance of these proteins, especially of APLP2, has been repeatedly shown by intense analysis of double and triple transgenic mice which lack APP in combination with one or both APLPs: several phenotypes such as defects in migration of neuroblasts, in formation of synapses and synaptic transmission have been reported. However, the specific contribution of either the uncleaved full-length proteins or their extracellular domains secreted upon ADAM10 activity has not been elucidated. In this review, we report on recent findings concerning shedding of APP-like proteins and resulting functional consequences.

Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging

“…It is well established that APP and APLPs can form homo-and heterodimers, arguing for a functional connection between these molecules (Soba et al 2005;Kaden et al 2011). APLP1 and APLP2 do not contain an Ab-domain, but their ectodomains are shedded in an ADAM10-dependent manner similar to that observed for APP (Jacobsen and Iverfeldt 2009;Endres and Fahrenholz 2011;Hogl et al 2011;Kaden et al 2011). In line with this hypothesis, neuroprotective IGF-1 signalling induces anti-amyloidogenic processing of APP and ectodomain shedding of APLP1 and APLP2 in human SH-SY5Y neuroblastoma cells (Adlerz et al 2007).…”

Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: Maintenance of brain iron homeostasis

“…The disintegrin metalloproteases, ADAM-10 (a disintegrin and metalloproteinase domain-containing protein 10), ADAM-17/tumor necrosis factor α-convertase (TACE), and ADAM-9, that have a consensus zinc binding motif, HEXXH, in their catalytic domain [29], fulfill some of the criteria required of α-secretases [6]. ADAM-10 interacts with synapse-associated protein-97 (SAP97) to prevent amyloidogenesis [30–32], decreases generation of toxic Aβ peptides, reduces senile plaques and alleviates learning deficits [33] in human APP transgenic mice (ADAM10 × APP[V717I]) [34]. …”

The effect of cadmium on Aβ levels in APP/PS1 transgenic mice

“…The results showed that the levels of these two proteins were significantly lower in the Cd treatment group. ADAM10 has a protective role in AD (20). Therefore, we speculated that Cd inhibits the activity of α-secretase, which leads to a greater metabolism of APP through the β-secretase pathway and an increase in Aβ.…”