Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid ß precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

Differential role of APP and APLPs for neuromuscular synaptic morphology and function.

The analysis of mouse models indicated that APP and the related APLPs are important for synapse formation and function. The synaptic role of APP is, however, complex due to partially overlapping functions within the gene family. APP/APLPs are proteolytically cleaved and have both adhesive and signaling properties. Mice lacking individual APP family members are viable, whereas APP/APLP2 and APLP1/APLP2 double knockout (DKO) mice die shortly after birth. Here, we analyzed the morphology of the neuromuscular junction (NMJ) of lethal APLP1/APLP2-DKO mice in comparison to lethal APP/APLP2-DKO mutants and viable single KO mice. We report that, surprisingly, the NMJ phenotype of APLP1/APLP2-DKO mice shows striking differences as compared to APP/APLP2-DKO mice. Unexpectedly, APLP1/APLP2-DKO mice exhibit normal endplate patterning and lack presynaptic nerve terminal sprouting. However, at the level of individual synapses we show that APLP1/APLP2-DKO mice exhibit reduced size of pre- and postsynaptic compartments and reduced colocalization. As APP/APLP2-DKO and APLP1/APLP2-DKO mice show similar penetrance of early postnatal lethality, this suggests that deficits at the level of individual synapses due to impaired synaptic apposition and/or deficits in transmitter release may cause lethality. Using an in vitro cell-adhesion assay, we observed that APP trans-dimerization is considerably less efficient than APLP2 trans-interaction. Thus, differences between APP/APLP2 and APP/APLP1 NMJ formation may be in part explained by differences in APP/APLP2 trans-dimerization properties. Collectively, our study further highlights the distinct and essential role of APLP2 at NMJ synapses that cannot be compensated by APP.

Roles of the amyloid precursor protein family in the peripheral nervous system.

Compelling evidence from in vivo model systems within the past decade shows that the APP family of proteins is important for synaptic development and function in the central and peripheral nervous systems. The synaptic role promises to be complex and multifaceted for several reasons. The three family members have overlapping and redundant functions in mammals. They have both adhesive and signaling properties and may, in principle, act as both ligands and receptors. Moreover, they bind a multitude of synapse-specific proteins, and we predict that additional interacting protein partners will be discovered. Transgenic mice with modified or abolished expression of APP and APLPs have synaptic defects that are readily apparent. Studies of the neuromuscular junction (NMJ) in these transgenic mice have revealed molecular and functional deficits in neurotransmitter release, in organization of the postsynaptic receptors, and in coordinated intercellular development. The results summarized here from invertebrate and vertebrate systems confirm that the NMJ with its accessibility, large size, and homogeneity provides a model synapse for identifying and analyzing molecular pathways of APP actions.

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

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 APPsα knock-in (KI) mice expressing solely the secreted ectodomain APPsα. Here, we generated double mutants (APPsα-DM) by crossing APPsα-KI mice onto an APLP2-deficient background and show that APPsα rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsα-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, APPsα-DM muscle showed fragmented post-synaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsα-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.