ArticleProceedings of the National Academy of Sciences of the United States of America2014
cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed, 139 citations in OpenAlex.
- Guanfacine treatment for prefrontal cognitive dysfunction in older participants: a randomized clinical trial.Neurobiology of aging · 2018Trial
- GLP-1R agonist semaglutide protects human forebrain organoids from cholesterol-induced neurotoxicity.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Inflammatory mechanisms underlying early Alzheimer's disease pathology: evidence from the aging rhesus macaque brain.Frontiers in cellular neuroscience · 2026Review
- Allosteric modulation of protein kinase A in individuals affected by NLPD-PKA, a neurodegenerative disease in which the PRKAR1B L50R variant is expressed.The FEBS journal · 2025Article
- Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.Cell reports · 2025Article
- The neuropathologic basis for translational biomarker development in the macaque model of late-onset Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2025Article
- Microglial galectin-3 increases with aging in the mouse hippocampus.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2025Article
- Connecting dots: Preclinical foundations to clinical realities of PDE4 inhibitors in Alzheimer's disease.Inflammopharmacology · 2025Review
- Marmosets as model systems for the study of Alzheimer's disease and related dementias: Substantiation of physiological tau 3R and 4R isoform expression and phosphorylation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Tau and tauopathies across primate species: implications for modeling neurodegenerative disorders.Frontiers in aging neuroscience · 2025Review
- Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation.Frontiers in aging neuroscience · 2025Article
- Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology.Frontiers in aging neuroscience · 2025Review
- Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Alzheimer's-specific brain amyloid interactome: Neural-network analysis of intra-aggregate crosslinking identifies novel drug targets.iScience · 2024Article
- Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease.Cerebral cortex (New York, N.Y. : 1991) · 2023Article
- Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders.Molecular psychiatry · 2023Review
- Interrogating the Etiology of Sporadic Alzheimer's Disease Using Aging Rhesus Macaques: Cellular, Molecular, and Cortical Circuitry Perspectives.The journals of gerontology. Series A, Biological sciences and medical sciences · 2023Article
- Cytomegalovirus infection induces Alzheimer's disease-associated alterations in tau.Journal of neurovirology · 2023Article
21 more citing papers are in PubMed but not listed here.
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14 authors at 2 institutions in 1 country.
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Abstract
The pattern of neurodegeneration in Alzheimer's disease (AD) is very distinctive: neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau selectively affect pyramidal neurons of the aging association cortex that interconnect extensively through glutamate synapses on dendritic spines. In contrast, primary sensory cortices have few NFTs, even in late-stage disease. Understanding this selective vulnerability, and why advancing age is such a high risk factor for the degenerative process, may help to reveal disease etiology and provide targets for intervention. Our study has revealed age-related increase in cAMP-dependent protein kinase (PKA) phosphorylation of tau at serine 214 (pS214-tau) in monkey dorsolateral prefrontal association cortex (dlPFC), which specifically targets spine synapses and the Ca(2+)-storing spine apparatus. This increase is mirrored by loss of phosphodiesterase 4A from the spine apparatus, consistent with increase in cAMP-Ca(2+) signaling in aging spines. Phosphorylated tau was not detected in primary visual cortex, similar to the pattern observed in AD. We also report electron microscopic evidence of previously unidentified vesicular trafficking of phosphorylated tau in normal association cortex--in axons in young dlPFC vs. in spines in aged dlPFC--consistent with the transneuronal lesion spread reported in genetic rodent models. pS214-Tau was not observed in normal aged mice, suggesting that it arises with the evolutionary expansion of corticocortical connections in primates, crossing the threshold into NFTs and degeneration in humans. Thus, the cAMP-Ca(2+) signaling mechanisms, needed for flexibly modulating network strength in young association cortex, confer vulnerability to degeneration when dysregulated with advancing age.
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