Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory
Introduction
The hallmark pathological features of Alzheimer's disease (AD) develop relatively late in the disease pathogenesis. To aid the development of effective therapeutic treatments for AD, the molecular alterations that initiate the onset of the AD pathogenic cascade must be identified (Walsh and Selkoe, 2004). One of the earliest physiological alterations of pathogenic consequence is an intracellular accumulation of soluble amyloid-β (Aβ), generated by altered processing of the parent amyloid precursor protein (APP) by β- and γ-secretases (Wirths et al., 2004, Haass and Selkoe, 2007). However, APP also produces other biologically active fragments, including the neurotrophic and neuroprotective protein secreted APPα (sAPPα) generated by α-secretase activity (Mattson, 1994, Turner et al., 2003). As α- and β-secretases can co-locate in the same proteolytic compartment, there is a competitive environment for the cleavage of APP (Skovronsky et al., 2000, Chyung and Selkoe, 2003, Shin et al., 2005) such that increased β-secretase activity during the pathogenesis of AD is accompanied by a decrease in the α-secretase cleavage of APP. Indeed, α-secretase activity is decreased and β-secretase activity is increased in post-mortem tissue from sporadic AD sufferers (Tyler et al., 2002). Furthermore, several studies have shown that sAPPα levels are decreased in the cerebrospinal fluid (CSF) of people with either familial (Lannfelt et al., 1995) or sporadic (Sennvik et al., 2000, Colciaghi et al., 2002, Post et al., 2006) forms of AD. Importantly, lowered levels of CSF sAPPα have been correlated with poor memory performance (Almkvist et al., 1997), an effect also seen in aged rats (Anderson et al., 1999).
The view that sAPPα has the capacity to contribute to normal memory function is supported by findings that exogenous administration of sAPPα or small peptide fragments of it enhances memory performance in mice, rats and chicks (Roch et al., 1994, Meziane et al., 1998, Bour et al., 2004, Mileusnic et al., 2004). Furthermore, exogenous sAPPα facilitates long-term potentiation (LTP) in vitro (Ishida et al., 1997). These findings contrast, however, with the reported effects of exogenous sAPPα in cultured neurons, such as a decrease in N-methyl-d-aspartate receptor (NMDAR) function, a facilitation of potassium channel activity, and a lowering of intracellular calcium levels (Furukawa et al., 1996a, Furukawa and Mattson, 1998), all of which would be expected to oppose LTP and memory formation. Given the discrepancies arising from exogenous sAPPα administration, and the potential relevance of decreased protein levels to AD pathogenesis and cognitive decline, it is important to understand the neural effects of reducing the activity of endogenous sAPPα. Studies using sAPP-targeted antibodies in rats and chicks have shown deficits in passive- and active-avoidance memory tasks (Doyle et al., 1990, Huber et al., 1993, Mileusnic et al., 2000), but the antibodies used did not distinguish the functions of sAPPα from related proteins such as sAPPβ (a less potent neurotrophic fragment generated by β- and γ-secretase processing). Here, we have used two strategies to target and inhibit endogenous sAPPα function in the hippocampus, and we have determined the effects of restoring sAPPα with exogenous recombinant protein.
Section snippets
Surgery
All experiments were conducted with the approval of the University of Otago Animal Ethics Committee, and in accord with New Zealand legislation. Adult male Sprague–Dawley rats (450–650 g) were anesthetized with urethane (2 g/kg, i.p.), placed into a stereotaxic frame, and maintained at 37 ± 0.3 °C. Using standard surgical procedures, pre-prepared recording electrode/cannula assemblies (75 µm stainless-steel wire glued to a 20 mm long 30 ga stainless-steel cannula) were lowered bilaterally into
Effects of sAPPα antibodies on LTP in vivo
The first experimental approach utilized a suite of APP antibodies to investigate the function of endogenous sAPPα on LTP. Of the three antibodies used, only anti-APP1 and anti-APP2 bind to sAPPα, as revealed by Western blot analysis of antibody binding to purified recombinant human sAPPα and sAPPβ (Fig. 1A). Importantly, anti-APP2 does not bind to sAPPβ (Fig. 1A). Anti-APP3 binds to an APP epitope that is cytoplasmically located and thus binds neither sAPPα nor sAPPβ (Fig. 1A). Since the
Discussion
We have used two independent approaches to demonstrate that endogenous sAPPα plays an important role in LTP induction processes in the rat dentate gyrus in vivo. First, we used antibodies that bind to different epitopes on APP, isolating the effect on LTP to the sAPPα domain of APP. Anti-APP1, which reduced LTP by nearly 50%, binds to full-length APP, sAPPβ and sAPPα, and has 80% recognition sequence homology for APLP2. Anti-APP2, which also binds sAPPα and APP but does not bind sAPPβ, APLP1 or
Acknowledgments
We gratefully acknowledge grant support from the New Zealand Health Research Council, the Neurological Foundation of New Zealand, the New Zealand Lottery Grants Board, and the Otago Medical Research Foundation to W.C.A. and W.P.T. We thank Amelia Gill, Desiree Dickerson and Barbara Logan for technical assistance with the watermaze experiment.
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Current address: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.