Soluble Amyloid Precursor Protein Alpha Interacts with alpha3-Na, K-ATPAse to Induce Axonal Outgrowth but Not Neuroprotection: Evidence for Distinct Mechanisms Underlying these Properties

Abstract

Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (Aß), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble N-terminal APP (sAPPα), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPPα are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (α3)-subunit of the plasma membrane enzyme Na, K-ATPase (NKA) as a new binding partner of sAPPα. We showed that sAPPα recruits very rapidly clusters of α3-NKA at neuronal surface, and its binding triggers a cascade of events promoting sAPPα-induced axonal outgrowth. The binding of sAPPα with α3-NKA was not observed for sAPPα-induced Aß1-42 oligomers neuroprotection, neither the downstream events particularly the interaction of sAPPα with APP before endocytosis, ERK signaling, and the translocation of SET from the nucleus to the plasma membrane. These data suggest that the mechanisms of the axonal growth promoting and neuroprotective properties of sAPPα appear to be specific and independent. The signals at the cell surface specific to trigger these mechanisms require further study.

Secreted Amyloid Precursor Protein-Alpha Promotes Arc Protein Synthesis in Hippocampal Neurons

“…A crucial, yet outstanding question in the literature is the identity of the ‘sAPPα receptor.’ Previous evidence has described a role of GABA B (Rice et al, 2017, 2019), Na/K ATP’ase (Dorard et al, 2018), α7nAch (Richter et al, 2018) and NMDA receptors (Gakhar-Koppole et al, 2008; Mockett et al, 2019) in mediating sAPPα’s plasticity enhancing effects. To understand the receptors contributing to the facilitated Arc expression, we investigated the possible contributions of these and other candidate receptors (mGluRI/II and TrkB) due to their similar neuromodulatory or plasticity-promoting properties (Raymond et al, 2000; Mockett et al, 2011).…”

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes

“…The electrophysiological model of learning, long-term potentiation (LTP), is modulated by sAPPα [ 26 , 30 , 31 , 32 , 34 , 35 ]. sAPPα promotes neurogenesis [ 36 , 37 ], neural cell proliferation [ 38 ] and can modulate dendritic spine density [ 39 ] and neurite outgrowth [ 40 , 41 , 42 , 43 ]. sAPPα also confers neuroprotection against hypoglycemia [ 44 ], amyloid beta (Aβ) toxicity [ 45 ] and glutamate toxicity [ 45 ].…”

Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases

“…Aβ precursor protein (APP) is cleaved by β-secretase and γ-secretase to produce Aβ peptides [ 51 ]. APP may also be cleaved by α-secretase and γ-secretase to produce soluble amyloid precursor protein α (sAPPα) [ 52 ]. It is interesting to observe that NKA acted as a modulator for both Aβ peptides and sAPPα to modulate learning and memory in AD [ 52 ].…”

“…APP may also be cleaved by α-secretase and γ-secretase to produce soluble amyloid precursor protein α (sAPPα) [ 52 ]. It is interesting to observe that NKA acted as a modulator for both Aβ peptides and sAPPα to modulate learning and memory in AD [ 52 ]. It was implied in recent studies that sAPPα recruited clusters of NKAα3 at neuronal surfaces.…”

“…The interaction of sAPPα and NKAα3 regulated the level of intracellular Na + and Ca 2+ that is required for APP to reach the cell surfaces. When APP interacted with sAPPα in the membrane, the APP/sAPPα complex triggered a cascade of events promoting sAPPα-induced axonal outgrowth [ 52 ]. However, the expression levels of sAPPα and NKA were significantly decreased in an AD rodent model compared with the control group [ 53 ].…”