Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo

Abstract

The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer's disease. Here, we studied whether the lack of APP affects the synaptic properties in the dentate gyrus by measuring granule cell field potentials evoked by perforant path stimulation in anesthetized 9-11-month-old APP-deficient mice in vivo. We found decreased paired-pulse facilitation, indicating altered presynaptic short-term plasticity in the APP-deficient dentate gyrus. In contrast, excitatory synaptic strength and granule cell firing were unchanged in APP knockout mice. Likewise, long-term potentiation (LTP) induced by a theta-burst stimulation protocol was not impaired in the absence of APP. These findings suggest that the deletion of APP may affect presynaptic plasticity of synaptic transmission at the perforant path-granule cell synapse but leaves synaptic efficacy intact and LTP preserved, possibly due to functional redundancy within the APP gene family.

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

“…APP expression is ~1.7× stronger at both mRNA and protein level in CA1 pyramidal cells compared to dentate granule cells. We propose that these differences in basal APP expression may contribute to the regional differences in APP function we reported in earlier studies using APP −/− animals (Ring et al, 2007; Jedlicka et al, 2012). …”

“…Adult (3–5 months old) male C57BL/6J mice (Janvier, France) and APP-deficient mice obtained from the colony at Heidelberg University (e.g., Li et al, 1996; Jedlicka et al, 2012) were used for experimental analysis. Animal care and experimental procedures were performed in agreement with the German law on the use of laboratory animals (animal welfare act; TierSchG).…”

“…Since the hippocampal formation and hippocampus-dependent learning and memory are affected early during the course of the disease (Braak and Braak, 1991) the hippocampus has been used as a model brain region to study the role of APP and its cleavage products in synaptic plasticity, learning and memory and neuroprotection (e.g., Turner et al, 2003; Ring et al, 2007). Interestingly, our physiological investigations of APP −/− mice revealed remarkable differences between the subregions of the hippocampus: whereas APP was necessary for long-term potentiation (LTP) at the CA3–CA1 synapse (Ring et al, 2007; Weyer et al, 2011; Hick et al, 2015) it was not essential for LTP at the entorhinal cortex-granule cell (EC-GC) synapse in the dentate gyrus (DG; Jedlicka et al, 2012). We speculated that regional differences in basal APP expression or APP processing could explain these phenotypic differences.…”

“…Together with in situ hybridization (ISH) data for APP, our results show that APP is expressed exclusively by hippocampal neurons under physiological conditions. It is ~1.7 fold higher expressed by CA1 pyramidal cells compared to dentate granule cells, which may contribute to the regional differences seen in electrophysiological studies of APP −/− mice (Ring et al, 2007; Jedlicka et al, 2012). …”

The physiological functions of the β-amyloid precursor protein APP

“…Moreover, it is clear that the full extent of APP in vivo functions for the developing and adult nervous system can only be assessed in the context of an intact, that is, whole, organism. Crucial insights have been obtained by studies in invertebrate and mammalian model organism including C. elegans, Drosophila and mice (see reviews in this issue by Ewald and Li 2011;Poeck et al 2011;Aydin et al 2011;Korte et al 2011;Jedlicka et al 2011;Jung and Herms 2011;Kogel et al 2011;Volknandt and Karas 2012). The impressive ease of genetic loss and gain of function screens in C. elegans and Drosophila establishes them as powerful model organisms.…”