Rapamycin promotes β-amyloid production via ADAM-10 inhibition

Abstract

Rapamycin is a well known immunosuppressant drug for rejection prevention in organ transplantation. Numerous clinical trials using rapamycin analogs, involving both children and adults with various disorders are currently ongoing worldwide. Most recently, rapamycin gained much attention for what appears to be life-span extending properties when administered to mice. The risk for Alzheimer disease (AD) is strongly and positively correlated with advancing age and is characterized by deposition of β-amyloid peptides (Aβ) as senile plaques in the brain. We report that rapamycin (2.5 μM), significantly increases Aβ generation in murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP). In concert with these observations, we found rapamycin significantly decreases the neuroprotective aminoterminal APP (amyloid precursor protein) cleavage product, soluble APP-α (sAPP-α) while increasing production of the β-carboxyl-terminal fragment of APP (β-CTF). These cleavage events are associated with decreased activation of a disintegrin and metallopeptidase domain-10 (ADAM-10), an important candidate α-secretase which opposes Aβ generation. To validate these findings in vivo, we intraperitoneal (i.p.) injected Tg2576 Aβ-overproducing transgenic mice with rapamycin (3 mg/kg/day) for 2 weeks. We found increased Aβ levels associated with decreased sAPP-α at an average rapamycin plasma concentration of 169.7 ± 23.5 ng/mL by high performance liquid chromatography (HPLC). These data suggest that although rapamycin may increase the lifespan in some mouse models, it may not decrease the risk for age-associated neurodegenerative disorders such as AD.

Rapamycin Delays Disease Onset and Prevents PrP Plaque Deposition in a Mouse Model of Gerstmann–Sträussler–Scheinker Disease

“…Rapamycin reduced the load of huntingtin aggregates and improved motor performance in a mouse model of HD (Ravikumar et al, 2004) and it reduced ␣-synuclein accumulation in PD transgenic mice (Crews et al, 2010). In addition, it was recently shown to improve cognitive deficits, decrease soluble A␤, and reduce A␤ plaque burden in some (Spilman et al, 2010;Yang et al, 2011), but not all (Zhang et al, 2010), transgenic mouse models of AD.…”

Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43

“…Indeed, induction of the autophagosome formation without parallel enhancement of the autophagic flux may result in further accumulation of aggregated protein and trigger more severe cytotoxicity. Such negative outcomes of the use of rapamycin as a therapeutic agent have also been found in other Alzheimer's disease animal models (26,27,34). Thus, autophagy activation by rapamycin and other autophagy-enhancing drugs may not be generally applicable for the treatment of different neurodegenerative diseases, and case-by-case studies should be carried out.…”

The Neurology of mTOR

“…Pharmacologic or genetic manipulations that decrease the amount of Aβ in mouse brain are associated with corresponding decreases in mTOR pathway activity(Caccamo et al, 2011). Inhibition of mTOR signaling has a beneficial effect on both pathophysiological and behavioral outcomes in several mouse models of Aβ pathology(Caccamo et al, 2011; Spilman et al, 2010; Zhang et al, 2010). Because of the important role of autophagy in the clearance of misfolded protein aggregates, autophagy dysfunction has been implicated in AD pathogenesis, and the stimulation of autophagy by mTOR inhibition is being tested as a potential therapeutic(Nixon, 2013).…”