Despite its description over years ago

Despite its description over 100years ago by German psychiatrist Alois Alzheimer, there has been little effective translation of insights on Alzheimer\'s disease (AD) pathobiology into effective treatments. As of 2015, roughly 50 million people globally — most over the age of 65years — have dementia, with AD accounting for 60–70% of cases. Already, AD is the sixth leading cause of death in the US and the leading killer of women in the UK. As the population ages, AD is expected to affect 135 million people by 2050. Within the formal healthcare system in the US, AD currently costs USD 236 billion per year, a number that does not account for over 18 billion unpaid hours by those family and friends voluntarily caring for AD patients. With June 2016, Alzheimer\'s Awareness Month, just behind us and the Alzheimer\'s Association International Conference convening July 24–28, 2016, now seems a good time to discuss the looming crisis of AD.
The recombinant parathyroid hormone (PTH) Teriparatide is the only therapy for postmenopausal gap 26 that increases bone mass (i.e., is anabolic). Its therapeutic action depends on a short “burst” of PTH in the circulation followed by a rapid return to normal levels; if PTH levels remain high, bone loss occurs (i.e., the effect is catabolic) (). This occurs because PTH not only stimulates the bone forming activity of osteoblasts, but also stimulates their ability to support osteoclast formation by producing RANKL. If PTH-induced RANKL production persists for longer than usual, anabolic intermittent PTH treatment can be switched to a catabolic effect (). This may explain why PTH therapy is not effective in all patients, and why PTH anabolic effect is not sustained with long-term treatment. Identifying mechanisms that control how PTH signalling is terminated within the cell may provide new ways to design PTH-based therapies to overcome this problem. Three recent papers including work in by Xiong et al. () indicate that PTH receptor signalling duration is controlled by VPS35 and SNX27, two components of the retromer complex. PTH signals through PTH receptor (PTH1R). This G protein-coupled receptor is shared with PTHrP (PTH-related protein), a paracrine factor produced by osteoblasts essential for normal physiological bone formation (). PTH or PTHrP binding to PTH1R initiates intracellular cyclic adenosine monophosphate (cAMP) signalling that continues as the receptor is internalised into endosomes. The signal is terminated by the acidic endosomal environment, which causes ligand dissociation, and by subsequent receptor recycling or degradation mediated by the multi-protein complex termed retromer (). Retromer has two known intracellular protein-transport functions. It carries protein cargo within endosomes, including internalised transmembrane receptors such as PTH1R, to the -Golgi network (); once the cargo reaches that destination it is recycled into components used by the cell to manufacture new proteins. The second function is to shuttle proteins within endosomes back to the plasma membrane, thereby restoring the transmembrane receptor availability. Retromer contains a heterotrimer of acuolar rotein orting-associated proteins VPS26, VPS29 and VPS35, and a dimer of membrane-associated orting ein (SNX) family members. These SNX family members sort proteins to the appropriate intracellular actin-mediated transport pathway. For instance, SNX27 directs traffic to the plasma membrane. SNX27 binds to the PTH1R through the SNX27 PDZ domain and tethers PTH1R to the VPS35-containing retromer complex (). PTH and PTHrP signalling could be modified by both functions of retromer. VPS35 knockdown in kidney cells () and osteoblasts () resulted in only a very slight elevation in the cAMP response to PTH. What is more convincing is an extended cAMP response duration reported in both studies, with cAMP levels remaining high until at least 40min after initial exposure to PTH. VPS35 deficiency might limit retrograde PTH1R transport, or impair trafficking to the plasma membrane: which of these is required to limit the cAMP response? VPS35 overexpression increased, and depletion reduced, PTH1R trafficking to the Golgi (). In addition, VPS35 or SNX27 depletion decreased PTH1R recycling rate at the plasma membrane following PTH treatment (). Both VPS35 and SNX27 knockdown increased cAMP accumulation (). Slower PTH1R recycling may therefore sustain cAMP accumulation without VPS35.