bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.10.11.617867

Mitochondrial Dysfunction in Alzheimer's Disease Is Driven By Excess ER-Calcium Release in Patient-Derived Neurons

Mustaly-Kalimi, S.·Gallegos, W.·Marr, R.·Peterson, D. A.·Sekler, I.·Stutzmann, G. E.
View original source ↗Export metadata ↓

Abstract

Tight regulation of mitochondrial Ca2+ is essential for neuronal bioenergetics and cellular metabolism. Ca2+ transfer from ER-localized ryanodine receptors (RyR) and inositol triphosphate receptors (IP3R) to the mitochondria maintains a steady Ca2+ source that fuels oxidative phosphorylation and ATP production. In Alzheimers disease (AD), RyR-evoked Ca2+ release is markedly increased, contributing to synaptic deficits, protein mishandling, and memory impairment. Here, we demonstrate that dysregulated RyR-Ca2+ release directly compromises mitochondrial activity and is an early contributor to AD cellular pathology. We measured an array of mitochondrial functions using fluorescent biosensors and optical imaging in RyR2-expressing HEK cells and iPSC-derived neurons from familial AD and nonAD patients. In neurons from AD patients, resting mitochondrial Ca2+ levels were elevated alongside increased free radical production and higher caspase-3 activity relative to nonAD neurons. RyR-evoked Ca2+ release further potentiated pathogenic mitochondrial responses in AD neurons, with increased Ca2+ uptake and exaggerated membrane depolarization. Additionally, clearance of damaged mitochondria was impaired in AD neurons, demonstrating consequences from dysfunctional lysosomes. Notably, impairments to mitochondria in AD neurons were largely prevented with the RyR negative allosteric modulator, Ryanodex. These findings highlight how excess RyR-Ca2+ release broadly contributes to early cellular pathology in AD which includes a cascade of ER, lysosomal, and mitochondrial deficits culminating in neuronal decline and degeneration. Additionally, pharmacological suppression of RyR-Ca2+ release preserves mitochondrial, ER and lysosomal function, thus providing a novel and effective therapeutic. Significance StatementMitochondrial dysfunction plays a central role in the cellular pathogenesis of Alzheimers disease, yet the upstream mechanisms driving these deficits remain largely unknown. Here, in human neurons derived from Alzheimers patients, we reveal how early Ca2+ mishandling through the ER-localized ryanodine receptor (RyR) is sensed by the mitochondria and triggers a pathogenic metabolic cascade. Pharmacologically restoring Ca2+ homeostasis reversed these deficits, including the increased free radicals and defective mitophagy, and restored the nonAD phenotype. The findings reveal the early neuronal signaling mechanisms that affect ER Ca2+ handling, proteolysis, and mitochondrial activity, highlighting the potential role of the dysregulated RyR as a therapeutic target for AD using clinically relevant model systems.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Mustaly-Kalimi, S., Gallegos, W., Marr, R., Peterson, D. A., Sekler, I., Stutzmann, G. E.. 2024-10-12. Mitochondrial Dysfunction in Alzheimer's Disease Is Driven By Excess ER-Calcium Release in Patient-Derived Neurons. https://doi.org/10.1101/2024.10.11.617867

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗
bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗
bioRxiv2026

Why Is Spontaneous Blink Timing Informative? An Adaptive Scheduling Perspective

Spontaneous eye blinks have long been linked to cognitive processing, yet how task demands shape blink timing and its relationship to behavioral performance remains unclear. We examined spontaneous blink behavior in 576 adults performing two variants of the Continuous Performance Task (CPT). Blink occurrence and timing were most strongly modulated by the experimental condition in the more demanding CPT-AX task, whereas their association with response time was stronger in the CPT-X task, where more consistent blink timing predicted faster responses. This dissociation suggests that task structure changes not only blink behavior but also the behavioral relevance of blink timing. These findings are consistent with an adaptive scheduling account of spontaneous blinking and provide a conceptual framework for understanding when and why blink timing contains chronometric information about ongoing cognition.

neuroscience↗