PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer's disease transgenic mice.

Abstract

Among the pathologic hallmarks of Alzheimer's disease (AD) neurodegeneration, only synaptic loss in the brains of AD patients closely correlates with the degree of dementia in vivo. Here, we describe a molecular basis for this AD loss of synapses: pathological reduction of synaptogenic PKC isozymes and their downstream synaptogenic substrates, such as brain-derived neurotrophic factor. This reduction, particularly of PKC α and ε, occurs in association with elevation of soluble β amyloid protein (Aβ), but before the appearance of the amyloid plaques or neuronal loss in the Tg2576 AD transgenic mouse strain. Conversely, treatment of the Tg2576 mouse brain with the PKC activator, bryostatin-1, restores normal or supranormal levels of PKC α and ε, reduces the level of soluble Aβ, prevents and/or reverses the loss of hippocampal synapses, and prevents the memory impairment observed at 5 months postpartum. Similarly, the PKC ε-specific activator, DCP-LA, effectively prevents synaptic loss, amyloid plaques, and cognitive deficits (also prevented by bryostatin-1) in the much more rapidly progressing 5XFAD transgenic strain. These results suggest that synaptic loss and the resulting cognitive deficits depend on the balance between the lowering effects of Aβ on PKC α and ε versus the lowering effects of PKC on Aβ in AD transgenic mice.

• Authors: Jarin Hongpaisan, Miao-Kun Sun, Daniel L Alkon
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 2 Pg. 630-43 (Jan 12 2011) ISSN: 1529-2401 [Electronic] United States
• PMID: 21228172 (Publication Type: Journal Article)

Chemical References

• 8-(2-(2-pentyl-cyclopropylmethyl)cyclopropyl)octanoic acid
• Amyloid beta-Peptides
• Brain-Derived Neurotrophic Factor
• Bryostatins
• Caprylates
• Enzyme Activators
• Isoenzymes
• bryostatin 1
• Protein Kinase C-alpha
• Protein Kinase C-epsilon

Topics

• Alzheimer Disease (metabolism, pathology, psychology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Bryostatins (pharmacology)
• Caprylates (pharmacology)
• Cognition Disorders (psychology)
• Enzyme Activators (pharmacology)
• Hippocampus (pathology)
• Isoenzymes (metabolism)
• Male
• Maze Learning
• Memory
• Mice
• Mice, Transgenic
• Plaque, Amyloid (pathology)
• Protein Kinase C-alpha (metabolism)
• Protein Kinase C-epsilon (metabolism)
• Synapses (pathology)