Dysregulated calcium signaling in the aged primate association cortices: Vulnerability to Alzheimer's disease neuropathology

Amy F T Arnsten^1*Isabella Perone¹Min Wang¹Shengtao Yang¹Stacy Uchendu¹Dinar Bolat¹Dibyadeep Datta^1,2

• ¹Department of Neuroscience, School of Medicine, Yale University, New Haven, United States
• ²Department of Psychiatry, School of Medicine, Yale University, New Haven, Connecticut, United States

This review will describe the magnification of calcium signaling in higher cortical circuits as a risk factor for AD pathology when calcium becomes dysregulated by age and inflammation. We will focus on the research from aging macaques, which have well-developed association cortices and naturally develop inflammation and tau, amyloid and synaptic pathology as well as autophagic degeneration of dendrites without the need for genetic mutations that cause autosomal dominant AD. The macaque model has the great advantage of allowing perfusion fixation to capture early stage, soluble tau pathology that is rapidly lost post-mortem (within 15min) and thus is only seen in human biopsy material. As macaques are APOE-e4 homozygotes, they also model the human subjects most vulnerable to AD. We will discuss how dysregulated calcium signaling can contribute to tau, amyloid and synaptic pathology as well as propelling autophagic degeneration, the process by which neurons die in AD. This information is key to developing therapeutic strategies to intervene at early stages to prevent AD.