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Amplified Protein Kinase C Signaling in Alzheimer's Disease
Author(s) -
Lorden Gema,
Wosniak Jacob M.,
Dozier Lara E.,
Patrick Gentry N.,
Gonzalez David J.,
Roberts Amanda J.,
Newton Alexandra C.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06842
Subject(s) - protein kinase c , marcks , dendritic spine , phosphorylation , cognitive decline , mutation , kinase , amyloid precursor protein , biology , alzheimer's disease , wild type , isozyme , signal transduction , microbiology and biotechnology , chemistry , medicine , endocrinology , biochemistry , disease , gene , enzyme , dementia , mutant , hippocampal formation
Protein kinase C (PKC) isozymes are tightly regulated kinases that transduce signals from receptor‐mediated hydrolysis of membrane phospholipids. Whereas loss‐of‐function mutations in PKC are associated with cancer, germline mutations that enhance the activity of one isozyme, PKCα, are associated with Alzheimer’s Disease (AD). Here we show that introducing a highly penetrant AD‐associated variant of PKCα (M489V; increases catalytic activity by 30%) into a mouse model accelerates brain pathogenesis and results in a cognitive defect compared to wild‐type mice. Specifically, behavioral studies reveal a cognitive impairment in mice harboring this mutation compared to WT mice at 12 months of age, as assessed by performance on a Barnes Maze test, which measures spatial learning and memory. Additionally, the presence of the PKCα mutation in an AD mouse model overexpressing the amyloid precursor protein with the Swedish mutation, significantly exacerbated the cognitive decline as early as 6 months of age. To better understand the molecular basis for the cognitive defect, we analyzed the phosphoproteome and synapse morphology of mice harboring the PKCα M489V mutation. Analysis of the brain phosphoproteome of PKCα M489V mice vs wild‐type mice identified a variety of substrates with altered phosphorylation including known substrates of PKC involved in synaptic depression. Phosphorylation of one such protein, MARCKS, was increased both in mice harboring the PKCα mutation as well as human brains from patients with AD. Analysis of spine density revealed a modest (approximately 10%) but highly significant reduction in the number of spines per micron in the homozygous M489V mice compared to the wild‐type mice. Reduced spine density is consistent with the enhanced phosphorylation of MARCKS observed in brains from the M489V mice. In summary, this work reveals that a single amino acid change in the catalytic domain of PKCα is sufficient to cause increased phosphorylation of PKC substrates, neurite degeneration, and cognitive decline. These data strongly support inhibition of PKCα as a potential therapeutic target in AD. Support or Funding Information Cure Alzheimer's Fund