Symposium
From Circuits to Models: Emerging Translational Approaches to Alzheimer’s Disease Across Species and Scales
Chair
Emilio Kropff
Leloir Institute Foundation - IIBBA/CONICET
Alzheimer’s disease (AD) is a multiscale disorder in which genetic susceptibility, vascular dysfunction, neural circuit abnormalities, and cognitive decline interact across time. Understanding these links requires experimental approaches that bridge molecular mechanisms, systems neuroscience, and translational animal models. This symposium brings together four complementary perspectives to examine how AD-related dysfunction emerges across species and levels of organization.
The session will begin with a discussion of major AD risk factors, including APOE4, MAPT, PICALM, and APP, focusing on how their interaction contributes to blood-brain barrier dysfunction, neurodegeneration, tauopathy, and amyloidosis, and on therapeutic strategies aimed at restoring neurovascular integrity. The second talk will then address circuit-level abnormalities, presenting evidence that abnormal high-frequency oscillations constitute an early signature of network hyperexcitability in AD, with converging findings from mouse models and human studies. The third talk will establish a physiological baseline in the South American rodent Octodon degus by characterizing hippocampal spatial coding, oscillatory dynamics, and sharp-wave ripple activity in young healthy animals. The final talk will expand this perspective by presenting Octodon degus as a natural model of brain aging and Alzheimer-like pathology, highlighting its potential for studying the links between aging, lipid metabolism, and neurodegeneration.
Together, these talks offer an integrated view of Alzheimer’s disease from genes and neurovascular mechanisms to neural dynamics and behavior, while also emphasizing the importance of innovative and complementary animal models. The symposium will highlight emerging translational opportunities for identifying early biomarkers, refining disease models, and advancing mechanistically informed therapeutic strategies.
Marcelo Coba
Keck School of Medicine, University of Southern California
Alzheimer’s genetic risk factors, neurovascular dysfunction and neurodegeneration: Therapeutical approaches
Alzheimer’s disease (AD) is a complex brain disorder, with more than 100 risk loci being identified. The interaction between factors is difficult to model, not only because of the interpretation of the mutations in the individual gene function, but also because these mutations are likely to impact different cell types at different stages of the disease. We will focus on the role of the main susceptibility gene for Alzheimer’s disease, Apolipoprotein E4 (APOE4) and the risk factors Microtubule Associated Protein Tau (MAPT), the Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM), and the Amyloid-beta precursor protein (APP). We will show their synergic interaction dysregulating blood brain barrier (BBB) function and increasing neurodegeneration. We will discuss tentative therapeutical approaches directed to restore BBB function and their impact on neurodegeneration, tauopathy and amyloidosis.
Christos Lisgaras
Department of Psychiatry, NYU Grossman School of Medicine
Brain Oscillations in Alzheimer’s Disease: Converging Evidence from Humans and Mouse Models
Neuronal oscillations are fundamental for coordinating brain activity across spatial and temporal scales, and disruptions in these rhythms emerge early in the Alzheimer’s disease continuum. In this talk, I will present translational findings from animal models and human studies demonstrating that abnormal high-frequency oscillations (HFOs; 250-500 Hz) represent an early signature of network hyperexcitability in Alzheimer’s disease. Using wideband electrophysiological recordings in mouse models, we identified HFOs as a previously unknown abnormality that arises before overt neuropathology and cognitive decline, with hippocampal circuits playing a central role in their generation. Extending these findings to humans, fast HFOs (>250 Hz) can be detected noninvasively during sleep in adults with Down syndrome, a population at ultra-high risk for Alzheimer’s disease. These results suggest that HFOs may serve as promising translational biomarkers of early circuit dysfunction in Alzheimer’s disease dementia.
Emilio Kropff
Leloir Institute Foundation - IIBBA/CONICET
Spatial coding in the hippocampus of young, healthy Octodon degus: a new avenue to investigate brain function during sporadic Alzheimer's disease
Octodon degus is a South American rodent that has attracted increasing interest as a model of aging and sporadic late-onset Alzheimer’s disease (AD). Spatial memory deficits have been reported in this species in association with advanced AD-like pathology or hippocampal lesions, underscoring its potential for investigating how hippocampal network function relates to behavioral performance across disease stages. Despite this promise, little is currently known about neural coding mechanisms in the degu brain. Here, we characterize neuronal activity and local field potential dynamics in young, healthy animals during (a) spatial navigation in open-field environments and (b) a novel object location task. We show that CA1 place cells exhibit properties comparable to those described in rats and mice, albeit with overall lower levels of spatial information. Although we did not identify object cells—known to be rare in the rat hippocampus—the introduction of an object elicited novelty-driven exploration accompanied by increased CA1 neuronal activity. We also characterize local field potential oscillations across multiple frequency bands, as well as sharp-wave ripple complexes. Together, these findings point to a shared organizational framework of hippocampal function and establish a foundation for future studies of age- and disease-related hippocampal dysfunction in this species.
Patricia Cogram
Institute of Ecology and Biodiversity (IEB), Faculty of Science, University of Chile,
Unconventional Animal Models of Alzheimer’s Disease: Insights from the Natural Aging Model Octodon degus
Understanding the mechanisms that link aging to Alzheimer’s disease (AD) remains one of the central challenges in neuroscience. While most experimental systems rely on genetically engineered models, a number of species naturally develop age-associated neuropathological and cognitive changes relevant to human neurodegeneration. The South American rodent Octodon degus has emerged as one of the most compelling natural models of brain aging and Alzheimer-like pathology. As they age, degus exhibit progressive cognitive decline together with key molecular features associated with AD, including amyloid deposition, tau alterations, neuroinflammation, and metabolic dysregulation. In this talk, I will present recent work characterizing Octodon degus as a translational model for studying the relationship between aging, lipid metabolism, and neurodegeneration. I will discuss comparative genomic insights, including variation in APOE and other genes involved in lipid transport and brain homeostasis, and how these findings may inform our understanding of Alzheimer’s disease susceptibility across species. These studies illustrate how unconventional animal models can complement traditional transgenic systems and provide new perspectives on the biological mechanisms underlying neurodegenerative disease.