Fluorescence and chemiluminescence imaging are the most widely applied optical emissive imaging

methods in biomedical research. “Smart” (turn-on) fluorescence imaging has been routinely used for in

vitro, cellular, and in vivo imaging; however, smart chemiluminescence imaging has been rarely explored.

In this report, we designed chemiluminescence probe ADLumin-1 and validated that ADLumin-1 was a

smart chemiluminescence probe for amyloid beta (Ab) species, evidenced by a 216-fold amplification of

chemiluminescence intensity upon mixing with Abs in vitro. In vivo two photon imaging indicated that

ADLumin-1 could efficiently cross blood-brain- barrier (BBB) and provided excellent contrast both for Ab

plaques and cerebral amyloid angiopathy (CAA). In vivo whole brain imaging showed that the

chemiluminescence signal of ADLumin-1 from 5-month-old transgenic AD (5xFAD) mice was 1.80-fold

higher than that from the age-matched wild-type mice. Moreover, we demonstrated that it was feasible to

further dually-amplify signal via chemiluminescence resonance energy transfer (DAS-CRET) using two

non-conjugated smart probes (ADLumin-1 and CRANAD-3) in solutions, brain homogenates, and in vivo

whole brain imaging. Our results showed that DAS-CRET could provide a 2.25-fold margin between 5-

month-old 5xFAD mice and wild type mice. To our knowledge, this is the first report that a

chemiluminescence probe could be used for detecting Ab species both in vitro and in vivo. Although

ADLumin-1 was designed for Abs, we believe that our strategy could be potentially extended to a wide

range of targets, including other aggregating-prone proteins. Notably, our results suggested that the

strategies for turning-on fluorescence could be used for amplifying chemiluminescence, and we believe that

our studies could inspire considerably more research on chemiluminescence imaging

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