Background: Alzheimer’s disease (AD) animal models have revealed neuroprotective actions
of Bryostatin-1 mediated by activation of novel PKC isoforms, suppression of beta-amyloid and
downregulation of inflammatory and angiogenic events, making Bryostatin-1 an attractive candidate
for attenuating AD-associated neural, vascular, and cognitive disturbances.
Objective: To further enhance Bryostatin-1 efficacy, nanoparticle-encapsulated Bryostatin-1 formulations
Methods: We compared nano-encapsulated and unmodified Bryostatin-1 in in vitro models of neuronal
PKC-d, PKC-e isoforms, α-secretase and studied nano-encapsulated Bryostatin-1 in an AD mouse
model of spatial memory (BC3-Tg (APPswe, PSEN1 dE9) 85Dbo/J mice).
Results: We found that nanoencapsulated Bryostatin-1 formulations displayed activity greater or equal
to that of unmodified Bryostatin-1 in PKC-δ and -ε and α-secretase activation assays. We next evaluated
how treatment with a nanoencapsulated Bryostatin-1 formulation facilitated spatial learning in the
Morris water maze. AD transgenic mice (6.5 to 8 months of age) were treated with nanoparticle encapsulated
Bryostatin-1 formulation (1, 2.5, or 5 μg/mouse) three times the week before testing and then
daily for each of the 5 days of testing. Across the acquisition phase, mice treated with nanoencapsulated
Bryostatin-1 had shorter latencies, increased % time in the target zone and decreased % time in
the opposite quadrant. The mice were given retention testing after a 2-week period without drug treatment.
Mice treated with nanoencapsulated Bryostatin-1 had shorter latencies to find the escape platform,
indicating retention of spatial memory.
Conclusion: These data suggest that cognitive deficits associated with AD could be treated using
highly potent nanoparticle-encapsulated formulations of Bryostatin-1.