Emerging Approaches to Enhance Neuronal Resistance Against Neurodegeneration
Date: October 19, 2026
Time: 10:15 am to 11:45 am
Room: Pacific Jewel Ballroom
Track: Plenary
Session Description
Age-related neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia—are traditionally viewed through pathogenic mechanisms such as protein aggregation, mitochondrial dysfunction, and chronic inflammation. An equally important but less explored dimension is neuronal resilience: the factors that enable certain neurons to resist or delay degeneration despite similar pathological exposure.
This session will bring together experts to highlight emerging approaches to studying neuronal resilience. Presentations will examine genetic, molecular, metabolic, and circuit-level determinants of neuronal vulnerability, and explore therapeutic strategies aimed at enhancing resilience rather than solely targeting pathology. The session aims to foster interdisciplinary dialogue and identify future directions for resilience-based therapeutic development.
Learning Objectives
At the conclusion of this session, attendees will be able to:
- Describe tools for unbiased assessment of neuronal resilience in neurodegeneration.
- Explain approaches to identify biological pathways and mechanisms through unbiased analyses.
- Identify model systems used to investigate mechanisms of neuronal resilience.
Speakers
- (Chair) Vikram Shakkottai, MD, PhD, FANA
- (Co-Chair) Mark S. Wainwright, MD, PhD, FANA
- (Speaker) Martin Kampmann, PhD
- (Speaker) Inma Cobos, MD, PhD
- (Speaker) Viviana Gradinaru, PhD
- (Speaker) Yagiz Altun, MD, PhD (2026 Emerging Scholar)
- (Awardee) Jorge Llibre-Guerra, MD
- (Awardee) Charles Windon, MD
Using CRISPR-based Functional Genomics in Human Neurons and Glia to Understand Resilience in Tauopathy
Description
The selective vulnerability and resilience of specific neuronal populations is a hallmark of neurodegenerative diseases. Understanding the underlying molecular mechanisms would not only provide novel insights in the molecular processes driving neurodegeneration, but could also pave the way for novel therapeutic approaches that promote neuronal resilience.
This presentation will present novel functional genomics approaches to uncover mechanisms of neuronal vulnerability and resilience. Specifically, participants will learn about unbiased CRISPR screening approaches in human iPSC models and mouse in vivo models of neurodegenerative diseases. I will present recent findings that we obtained using this platform with relevance to Alzheimer’s disease and other tauopathies: First, a characterization of cellular pathways controlling the accumulation of tau aggregates in human neurons, and second, discovery of a mechanism for tau toxicity in human neurons.
Attendees will leave with an understanding of the latest CRISPR-based functional genomics approaches to uncover mechanisms of neurodegenerative diseases, and new insights into the cellular pathways underlying tau aggregation and toxicity.
Identifying Molecular Signatures and the Functional Relevance of Resilience Factors in Alzheimer's Disease
Description
Selective neuronal vulnerability is a hallmark of Alzheimer’s disease (AD), yet the molecular mechanisms of neuronal resilience remain poorly understood. Single-nucleus transcriptomic profiling of the human neocortex has defined highly vulnerable populations depleted early in disease, including specific superficial-layer inhibitory interneurons and layer 2/3 excitatory neurons. Their loss disrupts circuit balance, contributing to cortical hyperexcitability. In contrast, layer 4 neurons remain relatively preserved into advanced disease stages despite residing in the same pathological microenvironments.
This presentation will examine selective vulnerability and resilience in the AD brain through single-cell and spatial multiomic profiling. Participants will review how integrated spatial and multiomic frameworks resolve pathological networks missed by single-modality analyses. Topics will include how local tissue microenvironments and neuronal-glial crosstalk modulate the transition from homeostatic states toward neurodegenerative or resilient phenotypes. We will show how spatial profiling of amyloid-beta plaques reveals coordinated protoplasmic astrocyte and microglial chemotaxis driving plaque compaction and the progression from diffuse to neuritic plaques, and how soma-seq profiling of neurons with neurofibrillary tangles (NFTs) differentiates NFT-specific molecular alterations from broader AD-associated changes, distinguishing between tau-dependent and tau-independent mechanisms of neurodegeneration.
Attendees will gain a clearer understanding of the interplay among depletion of specific neuronal subtypes, glial reactivity, and proteinopathic responses, along with practical insight into how integrative multiomic characterization and functional validation can identify vulnerable and resilient subtypes. These mechanisms provide a foundation for therapeutic strategies aimed at slowing disease progression and enhancing broader neuronal resistance to neurodegeneration.
Understanding Defense Mechanisms and Transport Across the BBB and Move Towards Targeted, Noninvasive Study and Repair of the Brain
Description
The brain is protected by the selective blood–brain barrier (BBB), which restricts access from circulating agents. Understanding the molecular mechanisms governing BBB transport could enable precise delivery to specific brain regions—and help anticipate how future pathogens might exploit this gateway.
This presentation will present a decade-long effort to develop a platform for mapping the molecular rules that govern movement from the bloodstream into the brain. The goal is to enable rational, noninvasive delivery of therapeutic and experimental agents. Using protein engineering—including directed evolution—and data science, we created adeno-associated viral vectors (AAVs) and non-viral shuttles capable of crossing the BBB. These vectors now support widespread transgene expression and enable advanced applications, such as in vivo whole-brain genetic screening.
Attendees will leave with a greater understanding of how this growing knowledge base—of both disease pathways and BBB entry mechanisms—offers promising strategies for identifying therapeutic targets and delivering safe, targeted interventions to the brain for both discovery and treatment.
Developmental Failure of Cortical Inhibition in Huntington's Disease: Implications for Early Therapeutic Intervention
Description
Although Huntington’s disease is traditionally viewed as a neurodegenerative disorder, growing evidence suggests that alterations in brain development may contribute to disease pathogenesis long before the onset of clinical symptoms. Defects in cortical interneurons and inhibitory circuitry may represent early drivers of neuronal dysfunction and provide novel opportunities for therapeutic intervention.
This presentation will examine how defects in cortical interneurons disrupt cortical inhibitory circuits in Huntington’s disease and explore the implications of these findings for early therapeutic intervention. Participants will review emerging evidence from human studies investigating the developmental origins of cortical dysfunction, examine the role of impaired inhibition in disease progression, and discuss potential treatment targets aimed at restoring circuit function before significant neurodegeneration occurs. Topics will also include the translational potential of these discoveries for developing earlier and more effective therapies.
Attendees will leave with a greater understanding of the role of developmental cortical circuit abnormalities in Huntington’s disease and practical insights into how targeting interneuron dysfunction may inform future disease-modifying therapeutic strategies.
Speakers
Awardee Remarks
