Secreted amyloid precursor protein-alpha can restore novel object location memory and hippocampal LTP in aged rats
Introduction
Amyloid precursor protein (APP) is a multifunctional Type 1 transmembrane protein expressed in both neurons and astrocytes. It has been suggested to act as a cell adhesion molecule (Breen, Bruce, & Anderton, 1991) as well as a G-protein coupled receptor (Deyts et al., 2016, Okamoto et al., 2001). When APP is cleaved by beta- and gamma-secretases, it generates both amyloid-beta, a significant contributor to the pathophysiology of Alzheimer’s disease (AD), and the soluble fragment amyloid precursor protein-beta (sAPPβ). The alternative processing of APP by the alpha-secretase ADAM10 precludes amyloid-beta generation and releases the APP ectodomain, secreted amyloid precursor protein-alpha (sAPPα), which is 16 amino acids longer than sAPPβ (for reviews see Kögel et al., 2012, Turner et al., 2003).
SAPPα is of particular interest as it has many growth factor-like properties, including being neurotrophic (Luo, Wallace, Hawver, Kusiak, & Wallace, 2001), neuroprotective (Mattson et al., 1993), neurogenic (Caille et al., 2004), an inducer of gene expression and protein synthesis (Claasen et al., 2009, Ryan et al., 2013, Stein et al., 2004), and memory enhancing (Anderson et al., 1999, Meziane et al., 1998). Recombinant sAPPα can also enhance long-term potentiation (LTP) in the hippocampus CA1 in vitro and the dentate gyrus in vivo (Ishida et al., 1997, Taylor et al., 2008). Moreover, lowering the concentration of endogenous sAPPα by APP knock-out or administration of the α-secretase inhibitor TAPI-1 causes memory and LTP deficits that can be rescued by intrahippocampal delivery of recombinant sAPPα (Hick et al., 2015, Taylor et al., 2008). For nearly all of these effects, sAPPα is a much more effective reagent than sAPPβ, indicating the importance of the α-secretase processing of APP in maintaining normal cognition and memory function. It is noteworthy, however, that an excess of recombinant sAPPα can inhibit LTP (Taylor et al., 2008), and if over-expressed during development, can generate cognitive and social interaction deficits that may be related to Fragile-X syndrome and autism spectrum disorders (Ray et al., 2011, Sokol et al., 2011).
Memory and LTP deficits are also prominent during normal aging, at least in a substantial proportion of animals and humans. In rodents, aging has been shown to be associated with impaired LTP induction in area CA1 (Landfield, McGaugh, & Lynch, 1978), impaired LTP persistence in the dentate gyrus (Barnes, 1979), as well as deficits in hippocampus-dependent tasks such as spatial reference memory, spatial working memory and object location memory (Geinisman, deToledo-Morrell, Morrell, & Heller, 1995). Interestingly, the levels of sAPPα have been reported to be reduced in the cerebrospinal fluid during aging in both rats and humans, and the level of sAPPα correlated well with cognitive performance (Almkvist et al., 1997, Anderson et al., 1999). In Alzheimer’s disease, most studies also report a decrease in cerebrospinal fluid sAPPα concentrations (Almkvist et al., 1997, Fellgiebel et al., 2009, Lannfelt et al., 1995, Olsson et al., 2003). Irrespective of whether sAPPα levels are actually reduced in aging or Alzheimer’s disease, sAPPα appears to have therapeutic potential for promoting recovery from neurological and cognitive dysfunction, as its acute administration can ameliorate the deficits produced by non-penetrating traumatic brain injury (Thornton, Vink, Blumbergs, & Van Den Heuvel, 2006). Accordingly, we have tested in the present study whether acute administration of recombinant sAPPα to the hippocampus can improve memory function and LTP in aged rats. We found that sAPPα could indeed enhance object location memory as well LTP in aged rats, while it was ineffective at causing similar improvements in young rats given the same regime of sAPPα delivery.
Section snippets
Materials and methods
All protocols were approved by the University of Otago Animal Ethics Committee. Male Long-Evans rats, aged (24 mo, 550–750 g) or young (5 mo, 500–650 g), were individually housed on a 12:12 light-dark cycle. Animals had access to dry food pellets and water ad libitum from weaning until one week prior to surgery, after which a diet of crushed food pellets and apple sauce food was given to restrict animals to 85% of body weight. For health reasons, animals remained on this diet for the duration of
Novel object location task
During the sample phase of the NOL task, aged animals explored the objects less than the young rats (F[1, 24] = 22.69, p < 0.001, 2 × 2 ANOVA; Table 1). However there was no main effect of sAPPα dose (F[1, 24] = 0.60, n.s.) nor an age × sAPPα dose interaction (F[1, 24) = 0.04, n.s.) on exploration. During the test phase, the aged animals again spent less overall time exploring the objects (F[1, 24] = 5.64, p = 0.026), and there was again no significant main effect of the sAPPα concentration nor an interaction of
Discussion
Our previous work in adult Sprague-Dawley rats in vivo revealed that recombinant sAPPα administered intrahippocampally can facilitate LTP in the dentate gyrus, and rescue watermaze spatial memory and dentate LTP from the deficits caused by the α-secretase inhibitor TAPI-1 (Taylor et al., 2008). Moreover, sAPPα (10 nM) applied to hippocampal slices from Sprague-Dawley rats significantly enhanced LTP in area CA1 (Ishida et al., 1997). The present study extended these findings to Long-Evans rats,
Acknowledgements
This research was supported by grants from the Health Research Council of New Zealand and the University of Otago Research Committee, New Zealand to W.C.A. and W.P.T, and by a Fulbright Foundation, U.S.A. scholarship to M.X. We thank Ms B. Logan for assistance with the surgical procedures.
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