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2017 ; 7
(1
): 4983
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English Wikipedia
A tricyclic antidepressant, amoxapine, reduces amyloid-? generation through
multiple serotonin receptor 6-mediated targets
#MMPMID28694424
Li X
; Wang Q
; Hu T
; Wang Y
; Zhao J
; Lu J
; Pei G
Sci Rep
2017[Jul]; 7
(1
): 4983
PMID28694424
show ga
Alzheimer's disease (AD) is a major and devastating neurodegenerative disease,
and the amyloid-? (A?) hypothesis is still the central theory for AD
pathogenesis. Meanwhile, another major mental illness, depression, is one of the
risk factors for AD. From a high-throughput screening (HTS), amoxapine, a typical
secondary amine tricyclic antidepressant (TCA), was identified to reduce A?
production. A follow-up investigation on antidepressants showed that most of the
TCAs harbour similar activity. Previous studies have indicated that TCAs improve
cognitive function in AD mouse models as well as in preliminary clinical data;
however, the underlying mechanism is controversial, and the effect on A? is
elusive. Thus, we developed a secondary screening to determine the molecular
target of amoxapine, and serotonin receptor 6 (HTR6) was identified. Knockdown of
HTR6 reduced the amoxapine's effect, while the HTR6 antagonist SB258585 mimicked
the activity of amoxapine. Further mechanistic study showed that amoxapine and
SB258585 reduced A? generation through multiple HTR6-mediated targets, including
?-arrestin2 and CDK5. Taken together, our study suggests that amoxapine, though
no longer a first-line drug for the treatment of depression, may be beneficial
for AD and further structural modification of TCAs may lead to desirable
therapeutic agents to treat both AD and depression.
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