Diated sorting may cause the decrease in TBRII levels previously observed in Rosiglitazone AD brain tissue [19]. Future studies should address whether the protein sorting functions of beclin 1 directly contribute to neuronal survival. TGF- signaling in AD is particularly interesting for the protection it may provide against some of the negative effects of A exposure. Treatment of primary cultures with TGF- protects against A-inducedO'Brien et al. Molecular Neurodegeneration (2015) 10:Page 11 ofneurotoxicity [17, 18], while pharmacological inhibition of ALK5 in rats exacerbates neurotoxicity of A oligomers injected into the hippocampus [17]. Inhibition of beclin 1-mediated TGF- signaling in AD may therefore sensitize neurons to A exposure and contribute to overt neuronal death. Prior to neuronal demise, TGF- may also protect against cognitive changes induced by A. A exposure impairs LTP in hippocampal slices [40], which may lead to the deficits in learning and memory observed in mouse models of AD [41]. TGF-, however, can positively modulate LTP. Treatment of hippocampal slices with TGF- prior to a weak stimulus converts early LTP to late-LTP, while pharmacological inhibition of ALK5 impairs LTP and cognitive performance in mice [14]. A decrease in beclin 1 levels and subsequent inhibition of TGF- signaling early in disease may therefore contribute to impaired LTP and decreases in cognitive function prior to neuronal death. Future studies should address whether decreased levels of beclin 1 impair LTP in both wild type and AD mouse models, as well as the potential therapeutic benefit of increased TGF- signaling in protecting against A-induced cognitive impairments. Given that beclin 1 reduces levels of the TGF- receptors, therapies that target TGF- signaling downstream of the receptors, rather than simply increasing ligand levels, may prove more efficacious. Our work presented here fits with an emerging literature that links dysregulation of protein trafficking pathways with neurodegeneration. Levels of VPS35 are decreased in AD [42], and mutations in VPS35 have been identified in patients with Parkinson's Disease (PD) [43, 44]. Mutations in the VPS10 receptor family proteins SorLA and SorCs, well-known retromer cargo that mediate trafficking of the amyloid precursor protein, have also been linked to AD [45?7]. Additionally, variants of CHMP2B, a component of the ESCRT machinery that functions in multivesicular body formation, are associated with frontotemporal dementia [48]. Looking more broadly within the endosomal system, mutations in Rab7 are associated with Charcot-Marie-Tooth Disease [49]. In addition to alterations in the trafficking machinery itself, variants in the microglial phagocytic receptor Trem2 that have been associated with neurodegenerative diseases including AD, PD, amyotrophic lateral sclerosis, and frontotemporal dementia impair maturation of this receptor [50]. These studies together strongly suggest that the proper endosomal trafficking of receptors in multiple cell types in the brain is critical for the maintenance of this organ and the prevention of neurological disease.important for neuronal homeostasis, including autophagy, growth factor signaling, and PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/17139194 protein sorting. Because beclin 1 functions in both autophagy and protein sorting, it represents an intriguing therapeutic target for neurodegenerative disease. Indeed, lentiviral delivery of beclin 1 in a mouse model of Parkinson's Disease was shown to protect against the loss.