Title:Nanoparticle-Encapsulated Bryostatin-1 Activates α-Secretase and PKC Isoforms In vitro and Facilitates Acquisition and Retention of Spatial Learning in an Alzheimer's Disease Mouse Model
Volume: 17
Issue: 14
Author(s): Lisa Schrott, Ping Yi, Kasey Jackson, Gabriel S. Jackson, Christopher Webb, Alireza Minagar, J. Winny Yun, Geoffrey Purdum, David J. Rios, Theodore A. Tyler, Maria I. Vizcanio, Judith L. Castor, Trevor Castor and Jonathan S. Alexander*
Affiliation:
- LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA,United States
Keywords:
Alzheimer's, dementia, secretase, PKC, neurodegenerative disease, cerebral cortex.
Abstract:
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
were prepared.
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.
