Title:The Intracellular Domain of Amyloid Precursor Protein is a Potential Therapeutic Target in Alzheimer’s Disease
Volume: 11
Issue: 4
Author(s): Hisashi Nagase and Kohzo Nakayama
Affiliation:
Keywords:
AICD, Alzheimer’s disease, amyloid precursor protein, APP signaling, intracellular domain,
Notch signaling, γ-secretase.
Abstract: Amyloid-β (Aβ) is widely believed to cause Alzheimer’s disease (AD), as it is the major
constituent of the amyloid plaques observed in the brains of people with AD (the so-called amyloid
hypothesis). Based on this hypothesis, therapies utilizing immune responses against Aβ have been
performed and have succeeded in effectively removing amyloid plaques, but have shown no
evidence of improvements in survival and/or cognitive function. Thus, it may be necessary to think
about this problem from a different viewpoint. γ-Secretase was initially identified as an enzyme that
cleaves amyloid precursor protein (APP) and produces Aβ. Although the primary function of
-secretase has not been fully clarified, this enzyme is well known to play a central regulatory role
in Notch signaling. After the shedding of the Notch ectodomain by metalloproteases, γ-secretase
releases the intracellular domain (ICD) of Notch, which immediately translocates to the nucleus to
modify the expression of certain genes. Recently, many type 1 transmembrane proteins have also
been reported as substrates for γ-secretase. Interestingly, several of these substrates may share a
γ-secretase-regulated signaling mechanism similar to that of Notch. Indeed, we have demonstrated
that the ICD of APP (AICD) induces dynamic changes in gene expression and neuron-specific
apoptosis, suggesting that APP also has a signaling mechanism that is closely linked with AD. In
this review, we first summarize the evidence that γ-secretase–regulated mechanisms similar to
Notch signaling may play wide-ranging roles in signaling events involving type 1 transmembrane
proteins, including APP. We also focus on the possibility that APP signaling is involved in the onset
and progression of AD. Based on these ideas, we hypothesize that APP signaling, especially AICD,
may be an attractive therapeutic target in AD.
