Amyloid Precursor Protein Protects Neuronal Network Function after Hypoxia via Control of Voltage-Gated Calcium Channels

Abstract

Acute cerebral ischemia and chronic neurovascular diseases share various common mechanisms with neurodegenerative diseases, such as disturbed cellular calcium and energy homeostasis and accumulation of toxic metabolites. A link between these conditions may be constituted by amyloid precursor protein (APP), which plays a pivotal role in the pathogenesis of AlzheimerЈs disease, but has also been associated with the response to acute hypoxia and regulation of calcium homeostasis. We therefore studied hypoxia-induced loss of function and recovery upon reoxygenation in hippocampal slices of mice lacking APP (APP Ϫ/Ϫ ) or selectively expressing its soluble extracellular domain (APPs␣-KI). Transient hypoxia disrupted electrical activity at the network and cellular level. In mice lacking APP, these impairments were significantly more severe, showing increased rise of intracellular calcium, faster loss of function, and higher incidence of spreading depression. Likewise, functional recovery upon reoxygenation was much slower and less complete than in controls. Most of these deficits were rescued by selective expression of the soluble extracellular fragment APPs␣, or by pharmacological block of L-type calcium channels. We conclude that APP supports neuronal resistance toward acute hypoxia. This effect is mediated by the secreted APPs␣-domain and involves L-type calcium channels.

The trans-Golgi network is a major site for α-secretase processing of amyloid precursor protein in primary neurons

“…The cleavage and shedding of the luminal, or ecto, domain of APP by the metalloprotease ␣-secretase is a key processing event, as it is considered to minimize the generation of the pathogenic A␤ peptides associated with Alzheimer's disease (38,39). In addition, soluble sAPP␣ is known to have neurotrophic (40) and neuroprotective (41)(42)(43) properties. APP cleavage by membrane-bound ␣-secretase can occur at the plasma membrane (13,44); however, other cellular location(s) of ␣-secretase cleavage remain poorly defined.…”

Distinct in vivo roles of secreted APP ectodomain variants APP sα and APP sβ in regulation of spine density, synaptic plasticity, and cognition

“…In the alternative, non-amyloidogenic pathway cleavage of APP within the Ab region by the major a-secretase ADAM10 (a disintegrin and metalloprotease) prevents Ab generation and liberates APPsa that is secreted into the extracellular space (Saftig & Lichtenthaler, 2015). While our previous studies and work from others indicated that APPsa has neurotrophic and neuroprotective effects, including synaptogenic, LTP facilitating and memory enhancing properties (Meziane et al, 1998;Ring et al, 2007;Taylor et al, 2008;Milosch et al, 2014;Weyer et al, 2014;Hick et al, 2015;Hefter et al, 2016;Plummer et al, 2016), only few and mostly conflicting studies have as yet addressed the functions of APPsb (Nikolaev et al, 2009;Li et al, 2010;Weyer et al, 2011;Chasseigneaux & Allinquant, 2012). An important and still unresolved question is whether in addition to neurotoxic Ab accumulation a concomitant reduction in APPsa level, or an altered APPsa/APPsb ratio may contribute to AD symptoms and pathogenesis (reviewed by Mockett et al, 2017).…”

“…In this regard, it will be crucial to know whether APPsa and APPsb, that is only 16 amino acids shorter than APPsa, serve largely similar or distinct, possibly even opposite physiological functions. While our previous studies and work from others indicated that APPsa has neurotrophic and neuroprotective effects, including synaptogenic, LTP facilitating and memory enhancing properties (Meziane et al, 1998;Ring et al, 2007;Taylor et al, 2008;Milosch et al, 2014;Weyer et al, 2014;Hick et al, 2015;Hefter et al, 2016;Plummer et al, 2016), only few and mostly conflicting studies have as yet addressed the functions of APPsb (Nikolaev et al, 2009;Li et al, 2010;Weyer et al, 2011;Chasseigneaux & Allinquant, 2012). So far, the molecular basis of any difference compared to APPsa remained unclear.…”

Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

“…Investigations by Yang et al (2009) yielded that deletion of APP in hippocampal neurons increased L-type voltage gated Ca 2+ channel (LTCC) levels and function underlying an altered GABAergic STP. Likewise, a recent report implied APP possibly via the APPsα fragment to stabilize Ca 2+ homeostasis by regulating inhibition of LTCCs (Hefter et al, 2016). Nevertheless, APLP1 deficiency causes no LTP deficit even though GABAergic inhibition is affected in APLP1-KO mice.…”