Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP

Abstract

Amyloidogenic processing of the amyloid precursor protein (APP) generates a large secreted ectodomain fragment (APPsβ), β-amyloid (Aβ) peptides, and an APP intracellular domain (AICD). Whereas Aβ is viewed as critical for Alzheimer's disease pathogenesis, the role of other APP processing products remains enigmatic. Of interest, the AICD has been implicated in transcriptional regulation, and N-terminal cleavage of APPsβ has been suggested to produce an active fragment that may mediate axonal pruning and neuronal cell death. We previously reported that mice deficient in APP and APP-like protein 2 ( APLP2 ) exhibit early postnatal lethality and neuromuscular synapse defects, whereas mice with neuronal conditional deletion of APP and APLP2 are viable. Using transcriptional profiling, we now identify transthyretin ( TTR ) and Klotho as APP/APLP2-dependent genes whose expression is decreased in loss-of-function states but increased in gain-of-function states. Significantly, by creating an APP knockin allele that expresses only APPsβ protein, we demonstrate that APPsβ is not normally cleaved in vivo and is fully capable of mediating the APP-dependent regulation of TTR and Klotho gene expression. Despite being an active regulator of gene expression, APPsβ did not rescue the lethality and neuromuscular synapse defects of APP and APLP2 double-KO animals. Our studies identify TTR and Klotho as physiological targets of APP that are regulated by soluble APPsβ independent of developmental APP functions. This unexpected APP-mediated signaling pathway may play an important role in maintaining TTR and Klotho levels and their respective functions in Aβ sequestration and aging.

APP physiological and pathophysiological functions: insights from animal models

“…Surprisingly, both phenotypes were found to be rescued by either a C-terminal truncation of apl-1 or the soluble N-terminus, showing that the highly conserved C-terminus is not required for apl-1 function in the worm [15,16]. This differs from the mammalian system in which the APP C-terminus is essential for viability on a nonredundant background (see discussion under 'KI models [18,19]. Hornsten et al [15] were unable to accomplish rescue using the Cterminus alone, indicating, together with the other rescue experiments, that the N-terminus is the primary functional domain of APL-1 in the worm.…”

“…For APP, there are two knockout (KO) alleles [28,29], one hypomorphic allele [30], two conditional alleles [31,32], four defined truncation KI alleles [18,19,33] and two C-terminal point mutation KI alleles reported [34,35].…”

“…The first model expresses APPsβ with a FLAG tag at the C-terminus named APPsβ-ki [18] ( Figure 3D). The second model, named APP/hAβ/mutC [19], expresses APP with a humanized Aβ region, including three FAD mutations (Swedish, Arctic and London) to facilitate Aβ production, and a frameshift mutation in the C-terminus that deletes the last 39 aa residues of APP ( Figure 3E).…”

The relevance of α-KLOTHO to the central nervous system: Some key questions

“…Interestingly, these include soluble Amyloid precursor protein, which upregulates α-Klotho expression (Li et al, 2010), indicating that in pathological amyloidogenic conditions such as Alzheimer's Disease, proper α-Klotho expression might be impaired. Consistently, α-Klotho is decreased in the serum and brain of AD animal models (Kuang et al, 2014;Massó et al, 2015) and also in the CSF of humans (Semba et al, 2014).…”

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

“…In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15)(16)(17).…”