APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP

Abstract

Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsa knock-in (KI) mice expressing solely the secreted ectodomain APPsa. Here, we generated double mutants (APPsa-DM) by crossing APPsa-KI mice onto an APLP2-deficient background and show that APPsa rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsa-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsa-DM muscle showed fragmented postsynaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsa-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABA A receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity.

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…Interestingly, the decrease in pTau levels parallels with a significant increase in the inactive form of glycogen synthase kinase-3β (GSK3β) (GSK3β phosphorylated at Ser9; Figure 4c), one of the main kinases involved in the pathogenic mechanisms of AD through the phosphorylation at multiple sites of tau (Mandelkow et al, 1992). As a decrease in APP may result detrimental for its contribution to synaptic plasticity and hippocampus-dependent memory (Goguel et al, 2011;Weyer et al, 2011), we analyzed the effect of CM-414 on APP in WT mice. As depicted in Supplementary Figure S6a, we demonstrated that CM-414 did not affect APP or C99 levels in WT mice after 5 days of treatment, whereas the same treatment significantly reduced the levels of both APP and C99 and Aβ 40 in Tg2576 mice (Supplementary Figure S6b).…”

Deciphering the mechanism underlying late-onset Alzheimer disease

“…Notably, however, APP was recently shown to be required for maintenance of distal synaptic connections in APP/APLP2 knockout mice. 119 Hence, the increase in APP synthesis-so far exclusively considered as a trigger of accelerated production of 'neuro toxic' Aβ peptides-may be a physiological reaction of neurons to ensure stabilization of their synapses under stress conditions.…”

“…Indeed, in a transgenic mouse model of AD, dystrophic axons associated with Aβ plaques remained continuous and connected to viable neuronal somata. 129 Nevertheless, the lack of stabilizing presynaptic proteins, including APP, 119 is expected to trigger synaptic disconnectiona well-described feature of early-stage AD pathophysiology. 130 Secondary impairments in mitochondrial transport and energy supply, 131 and aberrant maturation of autophagic vacuoles, 30 are likely to further promote axonal de generation and induce neuronal death.…”

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

“…This indicates that the gene trap alleles do not completely disrupt normal splicing of the gene and are not null alleles. Moreover, the production of soluble Appa-RFP and Aplp2-RFP fusion proteins may compensate for the loss of the full-length Appa and Aplp2 proteins, similar to studies in mice (Weyer et al, 2011). The ligand binding and adhesive activity of the extracellular domain of APP is important for its role in synaptogenesis, cell adhesion, and neurite outgrowth, but the exact biological function remains unclear (Jacobsen and Iverfeldt, 2009).…”

“…In addition, the sAPP peptide is sufficient to rescue molting and morphogenesis defects from loss of APL-1 in Caenorhabditis elegans and is suggested to function in a cell-nonautonomous manner (Hornsten et al, 2007). In mice, a knock-in allele that produces sAPPα exclusively rescues the postnatal lethality in APP/APLP2 double mutants (Weyer et al, 2011), suggesting that much of the normal biological function of the APP gene family can be mediated through the soluble extracellular domains. It is also intriguing that patients with AD display reduced levels of the sAPPα cleavage peptide (Lannfelt et al, 1995), raising the possibility that the sAPPα could contribute to the pathogenesis of AD.…”