Alzheimer's Disease Mouse Model Shows Amyloid-Beta Driven Disruption of Nuclear Pore Complex Function

Core Concepts

Accumulation of intracellular amyloid-beta in a mouse model of Alzheimer's disease leads to a reduction in nuclear pore complexes and disruption of nucleocytoplasmic compartmentalization, rendering neurons more vulnerable to inflammation-induced cell death.

Abstract

The study examines the impact of amyloid-beta (Aβ) on the structure and function of the nuclear pore complex (NPC) in a mouse model of Alzheimer's disease (AD). The key findings are:

Neuronal nuclei in the AppNL-G-F/NL-G-F (App KI) AD mouse model show a time-dependent reduction in the expression and distribution of nucleoporins (NUPs), the core proteins that make up the NPC. This reduction is observed as early as 4 months of age, prior to the formation of amyloid plaques.

The loss of NUPs, particularly NUP98 and NUP107, correlates with the accumulation of intracellular Aβ in App KI neurons. Inhibiting Aβ production using a γ-secretase inhibitor (DAPT) partially restores NUP levels, while adding oligomeric Aβ42 to wild-type neurons recapitulates the NUP loss.

The degradation of the nuclear permeability barrier due to NPC dysfunction leads to impaired nucleocytoplasmic compartmentalization. App KI neurons exhibit faster recovery of small fluorescent proteins (EGFP) in the nucleus after photobleaching, indicating increased passive diffusion across the nuclear envelope.

The disruption of nucleocytoplasmic transport renders App KI neurons more vulnerable to inflammation-induced necroptosis, a programmed cell death pathway that requires nucleocytoplasmic shuttling of key signaling proteins.

Collectively, the results demonstrate that Aβ-driven NPC dysfunction is an early event in the pathogenesis of Alzheimer's disease and contributes to neuronal vulnerability, providing a potential therapeutic target.

Stats

Aβ accumulation in App KI neurons increases by 50-100% compared to wild-type neurons from DIV7 to DIV28.
NUP98 and NUP107 levels are reduced by 30-50% in App KI neurons compared to wild-type neurons from DIV14 to DIV21.
The recovery rate of EGFP in the nucleus after photobleaching is 20-30% faster in App KI neurons compared to wild-type neurons.

Quotes

"Collectively, our data implicates Aβ in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target."
"Remarkably, only neurons exposed to oligomeric but not monomeric or fibrillar Aβ42 showed a reduction in intensity and coverage of NUPs and a corresponding increase in intracellular Aβ."
"Collectively, these Aβ coculture experiments strongly indicates that expression of Aβ is sufficient to trigger a reduction in NUP expression in neurons."

Key Insights Distilled From

Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer’s Disease

by Bansal,V. A.... at www.biorxiv.org 01-09-2024

https://www.biorxiv.org/content/10.1101/2024.01.08.574293v2

Deeper Inquiries

What other cellular processes or pathways might be disrupted by the Aβ-driven NPC dysfunction observed in this study, and how could they contribute to the pathogenesis of Alzheimer's disease

The Aβ-driven NPC dysfunction observed in this study could disrupt several cellular processes and pathways that are crucial for neuronal function and survival. One major consequence of impaired nucleocytoplasmic transport is the mislocalization of key transcription factors and regulatory proteins that are essential for gene expression and cellular homeostasis. This disruption can lead to dysregulation of gene expression, affecting the production of proteins involved in synaptic plasticity, neuronal signaling, and maintenance of neuronal networks. Additionally, impaired nucleocytoplasmic transport can impact the clearance of misfolded proteins and aggregates, contributing to the accumulation of toxic protein species within neurons. This protein aggregation is a hallmark of neurodegenerative diseases, including Alzheimer's disease, and can further exacerbate cellular dysfunction and neuronal damage. Overall, the Aβ-driven NPC dysfunction may disrupt multiple cellular pathways, leading to synaptic dysfunction, neuronal degeneration, and cognitive decline in Alzheimer's disease.

How might the loss of nucleocytoplasmic compartmentalization and increased vulnerability to necroptosis in App KI neurons impact synaptic function and neuronal network activity

The loss of nucleocytoplasmic compartmentalization and increased vulnerability to necroptosis in App KI neurons can have significant implications for synaptic function and neuronal network activity. Necroptosis, a programmed form of cell death, is triggered by various cellular stresses and can lead to the rapid destruction of neurons. In the context of Alzheimer's disease, the increased susceptibility of App KI neurons to necroptosis due to NPC dysfunction can result in the loss of neuronal populations, disrupting synaptic connectivity and network activity. This neuronal loss can impair the transmission of signals between neurons, leading to cognitive deficits and memory impairment. Furthermore, the dysregulation of nucleocytoplasmic transport can affect the localization of synaptic proteins and neurotransmitters, impacting synaptic transmission and plasticity. Overall, the combination of disrupted nucleocytoplasmic compartmentalization and increased necroptosis vulnerability in App KI neurons can have detrimental effects on synaptic function, neuronal network activity, and cognitive processes in Alzheimer's disease.

Could targeting the nuclear pore complex or restoring nucleocytoplasmic transport be a viable therapeutic strategy for Alzheimer's disease, and what challenges might arise in developing such an approach

Targeting the nuclear pore complex (NPC) or restoring nucleocytoplasmic transport could be a promising therapeutic strategy for Alzheimer's disease. By addressing the underlying NPC dysfunction and restoring proper nucleocytoplasmic transport, it may be possible to mitigate the cellular dysregulation and protein mislocalization observed in Alzheimer's disease. Restoring normal nucleocytoplasmic transport could help maintain the proper localization of key regulatory proteins and transcription factors, supporting normal gene expression and cellular function. Additionally, targeting the NPC could potentially reduce the accumulation of toxic protein aggregates and improve cellular clearance mechanisms, thereby reducing neuronal damage and degeneration.
However, there are several challenges that may arise in developing such an approach. One challenge is the complexity of the NPC and nucleocytoplasmic transport machinery, which involves multiple proteins and regulatory mechanisms. Targeting specific components of the NPC without disrupting normal cellular function could be challenging. Additionally, the blood-brain barrier may limit the delivery of therapeutic agents targeting the NPC to the brain, requiring innovative delivery strategies. Furthermore, the heterogeneity of Alzheimer's disease and the multifactorial nature of its pathogenesis may necessitate personalized therapeutic approaches targeting specific molecular pathways in individual patients. Despite these challenges, targeting the NPC and restoring nucleocytoplasmic transport holds promise as a potential therapeutic strategy for Alzheimer's disease.