Interrogating the Etiology of Sporadic Alzheimer's Disease using Aging Rhesus Macaques: Cellular, Molecular and Cortical Circuitry Perspectives.

Aging is the most significant risk factor for neurodegenerative disorders such as Alzheimer's Disease (AD) associated with profound socioeconomic and personal costs. Consequently, there is an urgent need for animal models that recapitulate the age-related spatial and temporal complexity and patterns of pathology identical to human AD. Our research in aging non-human primate (NHP) models involving rhesus macaques have revealed naturally occurring amyloid and tau pathology, including the formation of amyloid plaques and neurofibrillary tangles comprised of hyperphosphorylated tau. Moreover, rhesus macaques exhibit synaptic dysfunction in association cortices and cognitive impairments with advancing age, and thus can be used to interrogate the etiological mechanisms that generate neuropathological cascades in sporadic AD. Particularly, unique molecular mechanisms (e.g., feedforward cAMP-PKA-calcium signaling) in the newly evolved primate dorsolateral prefrontal cortex (dlPFC) are critical for persistent firing required for subserving higher-order cognition. For example, dendritic spines in primate dlPFC contain a specialized repertoire of proteins to magnify feedforward cAMP-PKA-calcium signaling such as NMDA receptors and calcium channels on the smooth endoplasmic reticulum (e.g., ryanodine receptors). This process is constrained by phosphodiesterases (e.g., PDE4) that hydrolyze cAMP and calcium-buffering proteins (e.g., calbindin) in the cytosol. However, genetic predispositions and age-related insults exacerbate feedforward cAMP-PKA-calcium signaling pathways that induce a myriad of downstream effects, including opening of K + channels to weaken network connectivity, calcium-mediated dysregulation of mitochondria and activation of inflammatory cascades to eliminate synapses, thereby increasing susceptibility to atrophy. Therefore, aging rhesus macaques provide an invaluable model to explore novel therapeutic strategies in sporadic AD.