Alzheimer’s disease (AD) has long been associated with altered activity of the
serine/threonine kinases, Glycogen Synthase Kinase-3 (GSK3) isozymes, which are
proposed to contribute to both neurofibrillary tangles and amyloid plaque formation.
While the molecular links between GS3K and tau pathology are well established, the
molecular basis by which GSK3 affects the formation of amyloid-β (Aβ) remains
unknown. The aim of this investigation was to identify the underlying mechanisms
by which inhibition of GSK3 affects the processing of the amyloid precursor protein
(APP).
To this end various methods were employed to alter the basal activity of the
GSK3 enzyme in N2a cells, a mouse neuroblastoma cell-line, overexpressing the
Swedish variant of APP. Specific perturbation of GSK3 activity leads to an
alteration in APP processing and Aβ production, something that until now, was seen
as controversial. Specific pharmacological inhibition of GSK3 resulted in a decrease
in activity, expression and transcription of BACE1, which is the main enzyme
responsible for Aβ generation. Activation of the canonical Wnt pathway, which is
associated with negative regulation of GSK3, reproduced the previous findings and
led to reduction in transcription and expression of BACE1.
Furthermore, specific pharmacological GSK3 inhibition and GSK3α/β
knockdown enhanced full-length APP degradation via an increase in the number of
lysosomes. This induction of the lysosomal/autophagy pathway was associated with
the effect of specific GSK3 inhibition on the nuclear translocation of transcription
factor EB (TFEB), which is a master regulator of lysosomal biogenesis.
All together, GSK3, in addition to being associated with hyperphosphorylation
of tau, can also influence Aβ generation through regulating BACE1
expression and the homeostatic turnover of APP. This data reinforces the hypothesis
that GSK3 could be a therapeutic target for AD as it is shown to be a central
signalling node in the pathogenesis of the disease
