Inhibition of the mTOR (mammalian Target of Rapamycin) signaling pathway by rapamycin extends lifespan in mice (Harrison et al. 2009) and protects against cognitive impairment in Alzheimer's disease (AD) transgenic mice (Caccamo et al. 2010; Spilman et al. 2010). At the same time, mTOR is an evolutionarily conserved, central regulating tyrosine kinase involved in multiple important physiological functions, including nutrient sensing, cell growth and metabolism, regulation of transcription and translation, autophagy, and synaptic plasticity.
In this issue, Pierce and colleagues (Pierce et al. 2012), provide new insights into a mechanism whereby mTOR inhibition might be beneficial for AD transgenic mice. The authors employed proteomic profiling using 2D electrophoresis to examine changes in chronic rapamycin treated compared with untreated Platelet derived growth factor promoter human amyloid precursor protein (PDAPP) AD transgenic mouse brains. Interestingly, structural, synaptic and vesicle transport proteins were prominent among proteins that were altered. Yet, they focused on alterations in chaperone proteins, as several altered proteins had chaperone activity. Of note, α-synuclein was among chaperone-like proteins changed significantly by rapamycin in AD transgenic mice. Turning then to known chaperone proteins, they determined by western blot that chaperones in AD transgenic mice were up-regulated by chronic rapamycin treatment. Despite the elevation in stress-activated chaperone proteins, transcription was only increased for alpha-B-crystallin. The authors noted that a previous study in C. elegans reported that alpha-B-crystallin reduced β-amyloid aggregation (Fonte et al. 2008). Because of the up-regulation in translation of stress-activated chaperones, the authors next turned to studying heat-shock protein 1 (HSF1). They found increases in activated HSF1 in rapamycin treated PDAPP mice. To test whether the beneficial effects of rapamycin on PDAPP mice were via activation of HSF1, they then crossed HSF1 over-expressing mice with PDAPP mice. Similar to rapamycin treatment, HSF1 over-expression led to reduced brain β-amyloid levels and improvement on tests of memory function in PDAPP mice. Thus, this interesting article provides new directions for research into the potentially important therapeutic target of mTOR in AD.
Aging is viewed as the most important risk factor for the development of AD, and it was thus of considerable interest that rapamycin treatment not only extended lifespan in wild type mice but also reduced amyloid pathology and improved behavior in AD transgenic mice (Caccamo et al. 2010; Spilman et al. 2010). The mechanisms whereby aging promotes the development of AD remains poorly understood, although evidence supports roles for elevated oxidative stress as playing an important role (Lin and Beal 2006). For example, reducing antioxidant defenses promotes amyloid pathology in AD transgenic mice (Li et al. 2004). Impaired protein degradation pathways also appear to play an important role in aging, and chaperone activity has been reported to decline with aging (Pierce et al. 2012). It is possible that rapamycin specifically acts via an up-regulation of chaperones that then reduce aberrant brain β-amyloid accumulation and cognitive impairment in AD models as the current article reports. Nevertheless, the signaling of mTOR, which is important in many central metabolic pathways, is complex. Thus, alternative effects of mTOR inhibition other than directly via chaperone activation may also be important in the benefits observed in AD mouse models. In addition, the AD research field increasingly worries about benefits observed in transgenic mouse models, as recent results on therapeutic translation from mice to humans has not been particularly encouraging. Here, one might want to consider whether mTOR inhibition directly affects the over-expressed mutant human APP in the AD transgenic mice. Pierce and colleagues, as well as prior articles, have shown no effect of rapamyicn treatment on total levels of APP in the brain of AD transgenic mice. Yet, one should consider that APP is compartmentalized within neurons. Although the predominant site of APP is the trans-Golgi network, increasing evidence supports that synapses are sites of attack in neurodegenerative diseases, and APP is trafficked and processed at synapses, which is regulated by synaptic activity. Interestingly, local translation of APP is regulated at synapses (Westmark and Malter 2007) and mTOR has been reported to regulate local protein synthesis important for long-term potentiation (LTP) at synapses (Tsokas et al. 2005). Moreover, β-amyloid was shown to co-localize with mTOR near synapses (Ma et al. 2010). Thus, it might be important to specifically look for local changes in the pool of APP and β-amyloid at synapses of AD transgenic mice in the setting of chromic rapamycin treatment.
In summary, mTOR and its interconnected signaling pathways well known to be important in many central cellular functions are now also increasingly appearing at the crossroads of aging, protein aggregation, and synapses, all of which are central to AD and therefore potentially for its treatment.