Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α–deficient mice

Abstract

<jats:p>Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic β-amyloid (Aβ) peptide generated from proteolytic cleavage of β-amyloid protein precursor (APP). Except for familial AD arising from mutations in the <jats:italic>APP</jats:italic> and presenilin (<jats:italic>PSEN</jats:italic>) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein α/calsyntenin1 (ALCα/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCα–X11L–APP tripartite complex suppresses Aβ generation <jats:italic>in vitro</jats:italic>, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCα in APP metabolism <jats:italic>in vivo</jats:italic> remains unclear. Here, by generating ALCα-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCα in the suppression of amyloidogenic processing of endogenous APP <jats:italic>in vivo</jats:italic>. We observed that ALCα deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic β-site cleavage of APP, especially in endosomes, and increases the generation of endogenous Aβ in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCα-deficient background. These results unveil a potential role of ALCα in protecting cerebral neurons from Aβ-dependent pathogenicity in AD.</jats:p>

Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria

“…CLSTN3 has been shown to mediate synapse development ( Pettem et al, 2013 ). Previous studies have also associated calsyntenins with neurodegeneration, specifically AD pathogenesis ( Gotoh et al, 2020 ; Uchida and Gomi, 2016 ; Vagnoni et al, 2012 ). There is also evidence for functional mammalian calsyntenins without the extracellular domain.…”

Deletion of Calsyntenin-3, an atypical cadherin, suppresses inhibitory synapses but increases excitatory parallel-fiber synapses in cerebellum

“…Moreover, carefully controlled immunoprecipitations showed that calsyntenins are present in a molecular complex with presynaptic GABA B -receptors and APP ( Dinamarca et al, 2019 ; Schwenk et al, 2016 ). However, Clstn1 KO mice exhibited only modest changes in APP transport and in the proteolytic processing of APP into Aβ peptides, and Clstn2 KO mice displayed no changes in these parameters ( Gotoh et al, 2020 ). Furthermore, the Clstn1 KO simultaneously increased the levels of the C-terminal cleavage fragment (CTF) of APP and of Aβ peptides without changing APP levels, making it difficult to understand how a decreased APP cleavage causing increased CTF levels could also elevate Aβ levels ( Gotoh et al, 2020 ).…”

“…However, Clstn1 KO mice exhibited only modest changes in APP transport and in the proteolytic processing of APP into Aβ peptides, and Clstn2 KO mice displayed no changes in these parameters ( Gotoh et al, 2020 ). Furthermore, the Clstn1 KO simultaneously increased the levels of the C-terminal cleavage fragment (CTF) of APP and of Aβ peptides without changing APP levels, making it difficult to understand how a decreased APP cleavage causing increased CTF levels could also elevate Aβ levels ( Gotoh et al, 2020 ). As a result, the kinesin binding, APP interaction, and GABA B -receptor complex formation by calsyntenins are well established, but it is not yet clear how these activities converge on a function for calsyntenins in axonal transport of APP.…”

Calsyntenin-3, an atypical cadherin, suppresses inhibitory basket- and stellate-cell synapses but boosts excitatory parallel-fiber synapses in cerebellum

“…Moreover, carefully controlled immunoprecipitations showed that calsyntenins are present in a molecular complex with presynaptic GABA B -receptors and APP (Dinamarca et al, 2019; Schwenk et al, 2016). However, Clstn1 KO mice exhibit only modest changes in APP transport or the proteolytic processing of APP into Aβ peptides, while Clstn2 KO mice display no change (Gotoh et al, 2020). Furthermore, the Clstn1 KO simultaneously increased the levels of the C-terminal cleavage fragment (CTF) of APP and of Aβ peptides without changing APP levels, making it difficult to understand how a decreased APP cleavage causing increased CTF levels could also elevate Aβ levels (Gotoh et al, 2020).…”

“…However, Clstn1 KO mice exhibit only modest changes in APP transport or the proteolytic processing of APP into Aβ peptides, while Clstn2 KO mice display no change (Gotoh et al, 2020). Furthermore, the Clstn1 KO simultaneously increased the levels of the C-terminal cleavage fragment (CTF) of APP and of Aβ peptides without changing APP levels, making it difficult to understand how a decreased APP cleavage causing increased CTF levels could also elevate Aβ levels (Gotoh et al, 2020). As a result, the kinesin binding, APP interaction, and GABA B -receptor complex formation by calsyntenins seem well established, but it is not yet clear how these activities converge on a function in axonal transport of APP.…”