The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models

Abstract

APP, APLP1, and APLP2 form a family of mammalian membrane proteins with unknown function. APP, however, plays a key role in the molecular pathology of Alzheimer's disease (AD), indicating that it is somehow involved in synaptic transmission, synaptic plasticity, memory formation, and maintenance of neurons. At present, most of our knowledge about the function of APP comes from consequences of AD-related mutations. The native role of APP, and even more of APLP1/2, remains largely unknown. New genetic knockout and knockin models involving several members of the APP/APLP family may yield better insight into the synaptic and systemic functions of these proteins. Here, we summarize recent results from such transgenic animals with special emphasis on synaptic plasticity and coherent patterns of memory-related network activity in the hippocampus. Data from APP knockout mice suggest that this protein is needed for the expression of long-term potentiation (LTP) in aged, but not in juvenile mice. The missing function can be rescued by expressing part of the protein, as well as by blocking inhibition. Double knockout mice lacking APP and APLP2 die shortly after birth indicating that different members of the APP/APLP family can mutually compensate for genetic ablation of single proteins. Recent techniques allow for analysis of tissue with combined defects, e.g., by expressing only part of APP in APLP2 knockout mice or by growing stem cells with multiple deletions on normal slice cultures. Data from these experiments confirm that APP and APLP2 do indeed play an important role in synaptic plasticity. Much less is known about the role of APP/APLP at the network level. Coherent patterns of activity like hippocampal network oscillations are believed to support formation and consolidation of memory. Analysis of such activity patterns in tissue from mice with altered expression of APP/APLP has just started and may shed further light on the importance of these proteins for cognitive functions.

APP Is Cleaved by Bace1 in Pre-Synaptic Vesicles and Establishes a Pre-Synaptic Interactome, via Its Intracellular Domain, with Molecular Complexes that Regulate Pre-Synaptic Vesicles Functions

“…This hypothesis is supported by in vitro data and studies with animal models, which have pointed to a synaptic function for APP and APP processing. Long Term Potentiation (LTP), a form of synaptic plasticity that underlies memory formation, is reduced in APP KO mice; furthermore, hippocampal APP KO neurons show increased size of the readily releasable synaptic vesicle pool and enhanced amplitudes of evoked AMPA- and NMDA-receptor-mediated responses [62]–[64]. Bace1 cleavage of APP is activated by synaptic activity and, as discussed earlier, generates the β-CTF APP metabolite that exerts a pathological role in mouse models of dementia.…”

From FMRP Function to Potential Therapies for Fragile X Syndrome

“…Genetic deletion of Arc in wild type and Fmr1 KO mice results in no significant mGluR1/5-LTD [125]. Another FMRP target, APP (amyloid beta precursor protein) [127] is also a structural protein that regulates synaptic function [128] as well as neurodegeneration. While overexpression of APP in Fmr1 KO mice increases seizure susceptibility [129], reduction of APP in Fmr1 KO mice rescues multiple FXS symptoms including AGS, higher density of immature spines, and the enhanced mGluR1/5-LTD [126].…”

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

“…The APP membrane receptor is involved in the regulation of neuronal activity, synaptic function, neurogenesis, and metal homeostasis. [20][21][22][23][24] APP undergoes proteolytic processing through two alternative cellular metabolic pathways, as illustrated in Figure 1. Aβ is produced through the so-called amyloidogenic pathway.…”

“…101,176 The function of the APP homologues remains unknown, but their expression in the central nervous system has been linked to synaptic plasticity and memory consolidation. 21 Their role in glucose metabolism and insulin homeostasis has also been documented. And the function of APP itself remains to be taken into consideration.…”