New Study Describes a Functional, Aged, Human Cell-Based Platform That Examines the Contribution of Senescence in Alzheimer’s Disease Progression, and Response to Therapeutics
30 Julio 2024 - 7:43AM
Business Wire
- Senescence role in AD established using a long-term
potentiation assay combined with biomarkers
- Human-on-a-Chip® platform models cognitive aging to evaluate
therapeutics
Researchers from Hesperos and the University of Central Florida
have developed a groundbreaking model using human induced
pluripotent stem cell (iPSC)-derived cortical neurons to better
understand and combat Alzheimer’s disease (AD). Their study, “A
functional aged human iPSC-cortical neuron model recapitulates
Alzheimer’s disease, senescence, and the response to therapeutics,"
has been published in the prestigious journal Alzheimer's &
Dementia®: The Journal of the Alzheimer's Association.
doi.org/10.1002/alz.14044
AD affects an estimated 6.2 million Americans aged 65 and older,
with projections suggesting this number could reach 14 million by
2050. Current treatments, such as acetylcholinesterase inhibitors
and NMDA receptor antagonists, provide only temporary relief. The
high failure rate of AD clinical trials highlights the need for a
better understanding of the pathophysiology and drug
mechanisms.
The study addresses a critical challenge in Alzheimer’s
research: the degeneration of cortical layers associated with
cognitive decline. Despite substantial efforts to date, few current
AD therapies are not disease-modifying. The team accurately
reproduced key biological aspects of aging and senescence in a
multi-cellular microphysiological system (MPS), also known as a
Human-on-a-Chip. This new approach reveals how cellular aging, also
known as senescence, contributes to disease progression and therapy
resistance, providing researchers with an accurate, human platform
to further understand the disease and potential therapeutics in a
living context.
Further, since other platforms at Hesperos, based on
neurodegenerative diseases, have been accepted by the Food and Drug
Administration (FDA) for efficacy data, it provides a new method to
accelerate development and regulatory submissions of new
treatments.
This model provides an invaluable tool for real-time measurement
of neuronal activity and aging biomarkers, facilitating drug
screening and the development of AD therapies. It also reveals
complex disease mechanisms, such as the role of inflammatory
factors in neuronal senescence and how it differs from non-disease
age-related controls, offering new targets for intervention.
Researchers cultured human iPSC-derived cortical neurons on
patterned microelectrode arrays to measure long-term potentiation
(LTP) noninvasively. LTP, a quantifiable metric for learning and
memory, is directly impacted by central nervous system
neurodegeneration. By treating these neurons with pathogenic
amyloid-β (Aβ), a peptide that plays a central role in development
of AD, to mimic disease pathophysiology, the team was able to
analyze senescence and therapeutic responses.
The study demonstrates that this novel human iPSC-cortical
neuron model of aging, cultured in serum-free, defined conditions,
accurately recapitulates hallmarks of AD showing the following:
- Pathological Insights: Aβ42 induced synaptic damage,
accelerated neuronal senescence, impaired mitochondrial potential,
and increased reactive oxygen species (ROS), leading to oxidative
stress and inflammation.
- Therapeutic Responses: Drugs such as memantine,
rolipram, saracatinib, and donepezil improved neuronal function and
viability, though they did not completely halt Aβ42-driven
senescence.
The study underscores the potential of biomimetic MPS systems in
translational research. By integrating clinically relevant neuronal
function with proteome responses, this platform is poised to
accelerate the discovery of novel neuroprotective compounds for AD
and other neurological disorders.
“This marks a significant step forward in Alzheimer's research
by providing a deeper understanding of AD pathophysiology in a
human aged MPS platform. We are excited about the potential of this
model to transform drug discovery in AD, providing hope for
patients,” said J. Hickman, PhD, co-founder and Chief Scientist of
Hesperos and Professor of Chemistry at UCF.
This research was supported by grants from the National
Institutes of Health (R44TR001326, R44AG058330).
Research Article: doi.org/10.1002/alz.14044
Nanoscience Technology Center (NSTC) at the University of
Central Florida (UCF)
The mission of the NSTC is to establish a cutting-edge research
program in materials and nanotechnology, provide high quality
training for students and facilitate the advance of innovations to
solve real world technology challenges.
https://nanoscience.ucf.edu/
Hesperos, Inc.
Hesperos is a global contract research organization (CRO)
providing drug development services using its Human-on-a-Chip®
platform - the most advanced, multi-organ microphysiological
systems available today. https://hesperosinc.com
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Nathan Post npost@hesperosinc.com 407-900-5915