THE QUEST FOR EARLY REVERSIBLE CHANGES IN ALZHEIMER'S DISEASE: MASS SPECTROMETRIC IMAGING OF GANGLIOSIDES IN A NOVEL TRANSGENIC RAT MODEL OF PRODROMAL AD

Abstract

Identifying the earliest cellular changes that lead to Alzheimer's disease (AD) is an important step towards preventing the disease. In search of such changes, we investigate membrane lipids called gangliosides that are essential for cell signaling and survival. The expression pattern of ganglioside species can change in response to stress, and in turn, altered membrane lipid composition can increase a cell's vulnerability to stressors. Gangliosides are implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), yet whether gangliosides play an important role in the earliest stages of AD development remains unresolved. We hypothesize that changes in membrane lipid composition, including gangliosides, may be evident in the elderly brain during the prodromal stages of AD. Such membrane alterations may render the aging brain more vulnerable, and set in motion a downward spiral of pathologic events, culminating in the development of AD. llIdentifying the earliest cellular changes that lead to Alzheimer's disease (AD) is an important step towards preventing the disease. In search of such changes, we investigate membrane lipids called gangliosides that are essential for cell signaling and survival. The expression pattern of ganglioside species can change in response to stress, and in turn, altered membrane lipid composition can increase a cell's vulnerability to stressors. Gangliosides are implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), yet whether gangliosides play an important role in the earliest stages of AD development remains unresolved. We hypothesize that changes in membrane lipid composition, including gangliosides, may be evident in the elderly brain during the prodromal stages of AD. Such membrane alterations may render the aging brain more vulnerable, and set in motion a downward spiral of pathologic events, culminating in the development of AD.the earliest cellular changes that lead to Alzheimer's disease (AD) is an important step towards preventing the disease. In search of such changes, we investigate membrane lipids called gangliosides that are essential for cell signaling and survival. The expression pattern of ganglioside species can change in response to stress, and in turn, altered membrane lipid composition can increase a cell's vulnerability to stressors. Gangliosides are implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), yet whether gangliosides play an important role in the earliest stages of AD development remains unresolved. We hypothesize that changes in membrane lipid composition, including gangliosides, may be evident in the elderly brain during the prodromal stages of AD. Such membrane alterations may render the aging brain more vulnerable, and set in motion a downward spiral of pathologic events, culminating in the development of AD. To model the prodromal stage of AD in the elderly brain, we use a novel transgenic rat strain. APP21 transgenic (tg) rats express human APP Swe/Ind in high quantities but do not develop histological hallmarks of AD spontaneously as they age. Yet, these animals are susceptible to developing pathological hallmarks of AD when challenged, for example with AD brain extracts. In brain sections from APP21 tg animals, we imaged and profiled gangliosides based on their chemical structure using matrix-associated-laser-desorption/ionization imaging mass spectrometry (MALDI-IMS). This innovative technology allows us to visualize changes in ganglioside expression profiles within a neuroanatomical context, and to relate these profiles to neuropathological events. To test our hypothesis, we harvested brains from APP21 tg rats and age-matched wildtype rats at different ages. Brain sections were imaged with MALDI-IMS and screened histologically for any pathology related to AD (Abeta, plaques, astrogliosis, activated microglia). A comparison of brain ganglioside expression between APP21 tg rats and wildtype animals will be presented. If our hypothesis is confirmed, an intervention aimed at stabilizing membrane lipid composition in individuals at risk of developing AD may make the aging brain more resistant to neurodegenerative challenges.