Abstract
The cellular prion protein (PrPC) is a key neuronal receptor for β-amyloid oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrPC shedding and increased AβO binding, which was blocked by the PrPC-specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrPC shedding and decreased AβO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AβO binding to PrPC. Besides blocking AβO binding and toxicity, acitretin also increased the nonamyloidogenic processing of APP. However, in the iPSC-derived neurons, Aβ and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrPC in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AβO, revealing a potential therapeutic benefit of ADAM10 activation in AD.
Highlights
The cellular prion protein (PrPC) is a key neuronal receptor for -amyloid oligomers (AO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer’s disease (AD)
In the presence of the ADAM10 inhibitor, carbachol failed to cause an increase in the shedding of PrPC (Fig. 1, A and B), indicating that carbachol was promoting the shedding of PrPC via activation of ADAM10
As cleavage of PrPC by ADAM10 regulates the amount of PrPC at the cell surface [31,32,33], we hypothesized that modulation of ADAM10 activity, through altering cell surface PrPC, would impact AO binding and toxicity
Summary
Several of the actions of AO, including activation of Fyn, dendritic spine loss, and tau phosphorylation, are mediated by PrPC coupling to mGluR5 [17,18,19], and pharmacological inhibition or allosteric modulation of mGluR5 reduced pathogenesis in AD mouse models [20, 21] Another approach has been to target Fyn directly with a specific inhibitor to rescue the memory deficits in an AD mouse model [22]. It is generally assumed that there is competition between the ␣- and -secretases for their substrate APP, resulting in a reciprocal relationship between the amyloidogenic and nonamyloidogenic APP-processing pathways In support of this reciprocal relationship, neuronal overexpression of ADAM10 in APPV717I transgenic mice increased the secretion of sAPP␣ and reduced the formation of A peptides [24], whereas in human induced pluripotent stem cell (iPSC)-derived neurons, inhibition of BACE1 reduced sAPP and A and increased sAPP␣ [25]. We report that acitretin reciprocally modulated the amyloidogenic and nonamyloidogenic processing of APP in neuroblastoma cells and rat hippocampal neurons, no such reciprocal relationship was observed in the human iPSCderived neurons
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