Biochemical characterization of age‐related calcium‐cAMP‐PKA signaling dysregulation and its effect on tau pathology in rhesus monkey cortex
Year: 2020
Type: article
Abstract: Background Early onset forms of Alzheimer’s disease (AD) are driven by rare dominantly inherited genes; however, the predominant form of the disease is sporadic and occurs later in life through an unknown etiology. Sporadic AD emerges after age 60‐65 and preferentially afflicts the association cortex. Thus, a better understanding of how age‐related changes in vulnerable brain regions relate to AD pathology is crucial to developing novel treatments for the disease. AD is characterized by two main pathological hallmarks, tau neurofibrillary tangles and amyloid‐beta plaques. Tau pathology correlates with cognitive decline while amyloid pathology does not. Thus, we focused on the role of age‐related signaling changes on tau pathology. Dysregulated calcium signaling has long been hypothesized to play a major role in age‐related vulnerability to AD1. Thus, we investigated the impact of aging on calcium signaling in the vulnerable dorsolateral prefrontal cortex (dlPFC) of rhesus monkeys, focusing on regulation of and by cAMP‐PKA signaling in relationship to tau pathology. Monkeys provide a unique opportunity to study higher order cognitive circuits unique to primates while still being able to probe molecular networks to a degree that is not possible in human post‐mortem samples. Overall, we found a significant age‐related dysregulation of calcium‐cAMP‐PKA signaling that strongly associated with early stage tau pathology in rhesus monkey dlPFC. (1) Khachaturian, Z. S. C Alzheimer’s & Dementia 13, 178‐182.e17 (2017) Method Patterns of molecular signaling were assessed via western blot and immuno‐electron microscopy of monkey dlPFC in animals ranging from 8 to 28 years of age. Mechanistic studies of the relationship between intracellular calcium and tau phosphorylation were performed in rat primary cortical cultures. Result We observed a consistent pattern of calcium‐cAMP‐PKA dysregulation in the vulnerable dlPFC region of rhesus monkeys. We found a highly significant association between leaky ryanodine receptor calcium channels and early stage tau phosphorylation (pS214 and pS356). The link between these phosphorylation sites and intracellular calcium was validated through in vitro mechanistic studies. Conclusion Age‐related dysregulation of calcium‐cAMP in the dlPFC is associated with early stage tau pathology and may explain the vulnerability of these circuits to degeneration.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.042017
Institution: Yale University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3111720340