GRK5KO Mouse Mirrors Mild Cognitive Impairment Due to Alzheimer's Disease

Alzheimer’s Disease (AD) poses a significant public health challenge due to its irreversible and progressive nature while lack of a cure. As a potential strategy to combat AD, its prevention becomes increasingly attractive. Mild Cognitive Impairment due to AD (MCI-AD) represents a critical transitional stage between normal age-related cognitive decline and more severe AD conditions, occurring just before dementia onset. Unfortunately, there is currently no established animal model that accurately recapitulates MCIAD characteristics. While many laboratories have traditionally used normally aged wild-type animals as experimental models, this approach falls short in representing the inherently worse state of MCI-AD compared to normal aging. To address this gap, we introduce an animal model-a transgenic mouse line with genetic inactivation of G protein-coupled Receptor Kinase-5 (GRK5), commonly known as the GRK5 Knockout (GRK5KO) mouse. These GRK5KO mice exhibit amnesia, cognitive deficits, in-creased β-amyloid levels, Neurofibrillary Tangle (NFT) immunopositive axonopathy and hippocampal neurodegenerative changes. Importantly, these pathological alterations predominantly impact the entorhinal, trans entorhinal and hippocampal cortices, aligning with human MCI-AD criteria and Braak stage II of human AD progression. Notably, female GRK5KO mice show approximately 2.5 times more NFT-positive axonopathy than males, mirroring the higher prevalence of AD cases in women. Collectively, existing data strongly supports the GRK5KO mouse as a qualified animal model for studying MCI-AD.

Author(s): William Z Suo

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