Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity

Abstract

The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission. Here, we generated animals with a conditional APP/APLP2 double knockout (cDKO) in excitatory forebrain neurons using NexCre mice. Electrophysiological recordings of adult NexCre cDKOs indicated a strong synaptic phenotype with pronounced deficits in the induction and maintenance of hippocampal LTP and impairments in paired pulse facilitation, indicating a possible presynaptic deficit. These deficits were also reflected in impairments in nesting behavior and hippocampus-dependent learning and memory tasks, including deficits in Morris water maze and radial maze performance. Moreover, while no gross alterations of brain morphology were detectable in NexCre cDKO mice, quantitative analysis of adult hippocampal CA1 neurons revealed prominent reductions in total neurite length, dendritic branching, reduced spine density and reduced spine head volume. Strikingly, the impairment of LTP could be selectively rescued by acute application of exogenous recombinant APPsα, but not APPsβ, indicating a crucial role for APPsα to support synaptic plasticity of mature hippocampal synapses on a rapid time scale. Collectively, our analysis reveals an essential role of APP family proteins in excitatory principal neurons for mediating normal dendritic architecture, spine density and morphology, synaptic plasticity and cognition.

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

“…On the presynaptic side, APP regulates the abundance of synaptic vesicle proteins and may impact on synaptic transmission (Laßek et al, 2013, 2014, Laßek et al, 2016a,b; Fanutza et al, 2015). This presynaptic effect is in line with our own findings, which indicate that lack of APP causes presynaptic changes at the EC-GC (Jedlicka et al, 2012) as well as the CA3-CA1 synapses (Hick et al, 2015). On the postsynaptic side, sAPPα, which is generated from APP by α-secretase cleavage, appears to be required for synaptic strengthening.…”

“…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.…”

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

“…Soluble APPa is upregulated during synaptogenesis and increases synaptic density, cortical synaptogenesis, and memory retention in vivo (Bell et al, 2008;Hick et al, 2015;Roch et al, 1994;Tyan et al, 2012), and it has been proposed to have both a neurotrophic and neuroprotective effect (Milosch et al, 2014;Mü ller and Zheng, 2012). The disintegrin metalloprotease ADAM10 is the constitutive a-secretase required for sAPPa generation (Kuhn et al, 2010).…”

Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases

“…Recently, numerous studies using iPSC-derived neurons have been published, including iPSC-derived neurons to model neurodegenerative diseases (Israel et al, 2012;Mattis et al, 2012;Kaye and Finkbeiner, 2013;Ryan et al, 2013;Richard and Maragakis, 2014). These proof-of principle studies recapitulate the key aspects of the different pathologies, including aberrant synaptic abnormalities and functional deficits (Penzes et al, 2011;Hick et al, 2014;Wen et al, 2014).…”