Microglia and mouse models of AD

The amyloid cascade hypothesis of Alzheimer's disease (AD) (as shown below) predicts that increased levels of Aβ peptides initiate a pathological cascade that results in tau pathology and eventually, neurodegeneration in susceptible brain regions. Impaired memory and reduced cognitive function leading to dementia are putative outcomes of Aβ-mediated neuronal damage.

Multiple pharmacological and vaccination–based therapies have been designed for AD, based primarily on research using mouse models of the disease. However, no single AD mouse model used in these past studies adequately recreates the characteristic pattern of pathologies observed in AD. The discrepancies between animal models of AD and humans with AD are troubling. Underlying tissue differences between mice and humans are a logical source of these disparate findings. In fact, one of the important differences between rodents and humans is the production of NO during the innate immune response. More information on this species specfic difference is found here.

By altering NO levels we also change the redox environment in mouse brain and disrupt essential protective mechanisms provided by NO. We have applied these concepts to generate a novel mouse model that provides unique insight into Alzheimer's disease and neurodegeneration in humans. Created by crossing the APPSw mouse that expresses mutated human amyloid precursor protein (APP) with a NOS2-/- mouse, our bigenic mouse model of AD increases expression of human Aβ on a murine NOS2 knockout background.

The phenotype at 52 weeks of age recreates the complete pathology observed in humans with AD, displaying high levels of Aβ

tau hyperphosphorylation, tau redistribution and tau aggregation within neuronal soma,

neuron loss,

behavioral deficits

and inflammation. A primary advantage of the APPSw/NO2-/- mouse is the formation of tau pathology from normal, unmutated tau and the presence of widespread neuron loss accompanied by behavioral deficits. Thus, our model provides a unique opportunity to test the amyloid cascade hypothesis in vivo under conditions of chronic disease. Our model also allows us to explore how nitric oxide contributes to the pathogenesis of AD.

In collaboration with Judianne Davis and Bill Van Nostrand of Stony Brook University in New York, we have developed a second AD model—in this case crossing NOS2-/- mice with the APPSwDI (Swedish K760N/M671L, Dutch E693Q and Iowa D694N) transgenic strain. The APPSwDI mouse has been well characterized by the Van Nostrand lab and was used in our study because it expresses low levels of APP and high levels of Aβ peptides in the brain. Since the triple-mutated APP produces Aβ peptides that cannot be transported out of the brain across the cerebrovascular interface, amyloid accumulates at the blood vessels. The APPSwDI mouse is now widely accepted as a model of cerebral amyloid angiopathy (CAA). CAA is found in 75-98% of the patients with AD, over 25% of whom are rated as severe CAA. The APPSwDI/NOS2-/- bigenic mouse is being used by my post-doctoral fellow (now an Assistant Professor at Duke), Dr. Donna Wilcock, to study the changes in neurovascular morphology in a mouse that also shows all of the pathological features of AD. This work will help decipher the role of vascular amyloid, astrocytes and cerebral blood vessels in the pathogenesis of AD. We are currently producing additional novel mouse strains to further understand how loss of NO and amyloid pathology can lead to neurodegeneration.

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