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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

[ Vol. 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*   Pages 1302 - 1310 ( 9 )

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.

Keywords:

Alzheimer's, dementia, secretase, PKC, neurodegenerative disease, cerebral cortex.

Affiliation:

LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA, Tongji Medical University - Medicine Wuhan, Hubei, Astellas Innovation Management LLC, Cambridge, Massachusetts, MA, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA, Aphios Corporation - R&D, Woburn, Massachusetts, MA, Aphios Corporation - R&D, Woburn, Massachusetts, MA, Aphios Corporation - R&D, Woburn, Massachusetts, MA, Aphios Corporation - R&D, Woburn, Massachusetts, MA, Aphios Corporation - R&D, Woburn, Massachusetts, MA, Aphios Corporation - R&D, Woburn, Massachusetts, MA, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, LA



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