Alzheimer’s disease (AD) is a neurodegenerative disorder
with multiple pathological features. Therefore, a multitarget-directed
ligands (MTDLs) strategy has been developed to treat AD. We have previously
designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a
novel tacrine derivative with acetylcholinesterase (AChE) inhibition
and brain-derived neurotrophic factor (BDNF) activation activity,
by linking tacrine and a fragment of huperzine A. However, it was
largely unknown whether A10E could act on other AD targets and produce
cognitive-enhancing ability in AD animal models. In this study, A10E
could prevent cognitive impairments in APP/PS1 transgenic mice and
β-amyloid (Aβ) oligomers-treated mice, with higher potency
than tacrine and huperzine A. Moreover, A10E could effectively inhibit
Aβ production and deposition, alleviate neuroinflammation, enhance
BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit
Aβ oligomers-induced neurotoxicity via the activation of tyrosine
kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore,
Aβ oligomerization and fibrillization could be directly disrupted
by A10E. Importantly, A10E at high concentrations did not produce
obvious hepatotoxicity. Our results indicated that A10E could produce
anti-AD neuroprotective effects via the inhibition of Aβ aggregation,
the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation,
and the decrease of AChE activity. As MTDLs could produce additional
benefits, such as overcoming the deficits of drug combination and
enhancing the compliance of AD patients, our results also suggested
that A10E might be developed as a promising MTDL lead for the treatment
of AD.
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