Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid‐β (Aβ)₄₂ peptides

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most frequent cause of dementia in the aged population. According to the amyloid hypothesis, the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of AD. Aβ is generated from the amyloidogenic processing of amyloid precursor protein and can aggregate to form oligomers, which have been described as a major synaptotoxic agent in neurons. Dysfunction of Wnt signaling has been linked to increased Aβ formation; however, several other studies have argued against this possibility. Herein, we use multiple experimental approaches to confirm that the inhibition of Wnt signaling promoted the amyloidogenic proteolytic processing of amyloid precursor protein. We also demonstrate that inhibiting Wnt signaling increases the production of the Aβ peptide, the Aβ /Aβ ratio, and the levels of Aβ oligomers such as trimers and tetramers. Moreover, we show that activating Wnt signaling reduces the levels of Aβ and its aggregates, increases Aβ levels, and reduces the Aβ /Aβ ratio. Finally, we show that the protective effects observed in response to activation of the Wnt pathway rely on β-catenin-dependent transcription, which is demonstrated experimentally via the expression of various 'mutant forms of β-catenin'. Together, our findings indicate that loss of the Wnt signaling pathway may contribute to the pathogenesis of AD.

BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

“…This model is supported by a recent report showing that inhibition of Wnt signalling induces amyloidogenic processing and aggregation of Aβ 42 peptides. 61 Thus, notwithstanding the limitations of transgenic models, the reduction in soluble Aβ 42 observed here is significant, as dementia severity correlates more closely with presence of soluble Aβ, rather than with fibrillar Aβ deposits in the brain. 62 …”

Morphological Neurite Changes Induced by Porcupine Inhibition Are Rescued by Wnt Ligands

“…A series of small molecule inhibitors speci cally target several of the proteins in the Wnt signaling pathway, such as Fzd, DVL, PORCN or Tankyrase, and could also be used as chemical probes to dissect the mechanism(s) of these signaling pathways (37,38). We therefore used Wnt-C59, a PORCN inhibitor, in young hippocampal neurons, to research polarization, the development of dendritic trees, and maintenance and/or maturation of dendritic spines; these inhibitory molecules have the potential to be developed both as study reagents in cell biology as therapeutic agents (39,40).…”

Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

“…However, from the perspective of AD as a progressive disease, Wnt signaling modulation may be important in vivo. In this regard, it is notable that aberrant Wnt signaling is a prominent feature in aging and several brain diseases [121,122], including AD [123][124][125][126][127][128][129][130][131][132]. One underlying cause of Wnt-signaling-pathway defects in AD progression is that Wnt signaling represses the transcript levels of BACE1.…”

“…In N2a cells, over-expression of Wnt agonist reduced Aβ levels and BACE1 expression, while over-expression of SFRP1 resulted in the opposite effect [126]. Loss of Wnt signaling would thus promote amyloidogenic APP processing, Aβ production [127,132], and downstream pathological events [128,129]. Given that it is an important Wnt signaling inhibitor [106], SFRP1 s inhibition or downregulation could therefore alleviate Aβ pathogenicity [125,132] somewhat independently of its inhibition of ADAM10 and non-amyloidogenic APP processing.…”