Rapamycin promotes beta-amyloid production via ADAM-10 inhibition.

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 beta-amyloid peptides (Abeta) as senile plaques in the brain. We report that rapamycin (2.5muM), significantly increases Abeta 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 amino-terminal APP (amyloid precursor protein) cleavage product, soluble APP-alpha (sAPP-alpha) while increasing production of the beta-carboxyl-terminal fragment of APP (beta-CTF). These cleavage events are associated with decreased activation of a disintegrin and metallopeptidase domain-10 (ADAM-10), an important candidate alpha-secretase which opposes Abeta generation. To validate these findings in vivo, we intraperitoneal (i.p.) injected Tg2576 Abeta-overproducing transgenic mice with rapamycin (3mg/kg/day) for 2weeks. We found increased Abeta levels associated with decreased sAPP-alpha at an average rapamycin plasma concentration of 169.7+/-23.5ng/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.

Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD).

Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD). HIV promotion of an M1 antigen presenting cell (APC) - like microglial phenotype, through the promotion of CD40 activity, may impair endogenous mechanisms important for amyloid- beta (Aß) protein clearance. Further, a chronic pro-inflammatory cycle is established in this manner. CD45 is a protein tyrosine phosphatase receptor which negatively regulates CD40L-CD40-induced microglial M1 activation; an effect leading to the promotion of an M2 phenotype better suited to phagocytose and clear Aß. Moreover, this CD45 mediated activation state appears to dampen harmful cytokine production. As such, this property of microglial CD45 as a regulatory "off switch" for a CD40-promoted M1, APC-type microglia activation phenotype may represent a critical therapeutic target for the prevention and treatment of neurodegeneration, as well as microglial dysfunction, found in patients with HAD.

Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice.

Extracellular plaques of beta-amyloid (Abeta) peptides are implicated in Alzheimer's Disease (AD) pathogenesis. Abeta formation is precluded by alpha-secretase, which cleaves within the Abeta domain of APP generating soluble APP-alpha (sAPP-alpha). Thus, alpha-secretase upregulation may be a target AD therapy. We previously showed green tea derived EGCG increased sAPP-alpha in AD mouse models. However, the comparable effective dose of EGCG in humans may exceed clinical convenience and/or safety. Epidemiological studies suggested fish oil consumption is associated with reduced dementia risk. Here we investigated whether oral co-treatment with fish oil (8mg/kg/day) and EGCG (62.5mg/kg/day or 12.5mg/kg/day) would reduce AD-like pathology in Tg2576 mice. In vitro co-treatment of N2a cells with fish oil and EGCG enhanced sAPP-alpha production compared to either compound alone (P<0.001). Fish oil enhanced bioavailability of EGCG versus EGCG treatment alone (P<0.001). Fish oil and EGCG had a synergetic effect on inhibition of cerebral Abeta deposits (P<0.001) suggesting moderate supplementation with EGCG and fish oil having significant therapeutic potential for the treatment of AD.