Impaired behavioural flexibility related to white matter microgliosis in the TgAPP21 rat model of Alzheimer disease.

Executive dysfunction and white matter inflammation continue to be relatively understudied in rodent models of Alzheimer's disease (AD). Behavioural inflexibility is an important component of executive dysfunction that can be further categorized as perseverative or regressive, which respectively specify whether maladaptive persistence occurs early or late during a behavioural change. Previous studies of the TgAPP21 rat model of AD (expressing pathogenic hAPP) suggested a potentially spontaneous increase of regressive behavioral inflexibility. In this study, 7-8-month-old male TgAPP21 rats were tested for behavioral flexibility, learning, and memory using an operant conditioning chamber and the Morris Water Maze (MWM). TgAPP21 rats demonstrated a regressive behavioral inflexibility during set shifting in an operant conditioning chamber (regressive errors η2 = 0.32 and number of errors after criterion η2 = 0.33). Regressive behavior was also demonstrated in the MWM probe test, wherein TgAPP21 rats significantly increased their swim time in the target quadrant during the last third of the probe test (43% vs 33% in the first 2 thirds of the probe test or the Wt rats' 29%-32%); this behavioral phenotype has not been previously described in the MWM. TgAPP21 demonstrated further impairment of behavioural inflexibility as they committed a greater number of reversal errors in the operant conditioning chamber (η2 = 0.30). Diffuse microglia activation was increased in the white matter tracts of TgAPP21 (corpus callosum, cingulum, and internal capsule; η2 = 0.59-0.62), which was found to correlate with the number of reversal errors in the operant conditioning chamber (R2 = 0.42). As TgAPP21 rats do not spontaneously develop amyloid plaques but have been shown in previous studies to be vulnerable to the development of plaques, these rats demonstrate an important onset of cognitive change and inflammation in the pre-plaque phase of AD. TgAPP21 rats are also an instrumental model for studying the role and mechanism of white matter microglial activation in executive functioning. This is pertinent to clinical research of prodromal AD which has suggested that white matter inflammation may underlie impairment of executive functions such as behavioral flexibility.

Membrane-lipid homeostasis in a prodromal rat model of Alzheimer's disease: Characteristic profiles in ganglioside distributions during aging detected using MALDI imaging mass spectrometry.

BACKGROUND: Accumulation of simple gangliosides GM2 and GM3, and gangliosides with longer long-chain bases (d20:1) have been linked to toxicity and the pathogenesis of Alzheimer's disease (AD). Conversely, complex gangliosides, such as GM1, have been shown to be neuroprotective. Recent evidence using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) has demonstrated that a-series gangliosides are differentially altered during normal aging, yet it remains unclear how simple species are shifting relative to complex gangliosides in the prodromal stages of AD. METHODS: Ganglioside profiles in wild-type (Wt) and transgenic APP21 Fischer rats were detected and quantified using MALDI-IMS at P0 (birth), 3, 12, and 20 months of age and each species quantified to allow for individual species comparisons. RESULTS: Tg APP21 rats were found to have a decreased level of complex gangliosides in a number of brain regions as compared to Wt rats and showed higher levels of simple gangliosides. A unique pattern of expression was observed in the white matter as compared to gray matter regions, with an age-dependent decrease in GD1 d18:1 species observed and significantly elevated levels of GM3 in Tg APP21 rats. CONCLUSIONS: These results are indicative of a pathological shift in ganglioside homeostasis during aging that is exacerbated in Tg APP21 rats. GENERAL SIGNIFICANCE: Ganglioside dysregulation may occur in the prodromal stages of neurodegenerative diseases like AD.

Age-dependent and regional heterogeneity in the long-chain base of A-series gangliosides observed in the rat brain using MALDI Imaging.

Alterations in the long chain base of the sphingosine moiety of gangliosides have been shown to play a role in neurodevelopment and neurodegeneration. Indeed, the accumulation of d20:1 sphingosine has been referred to as a metabolic marker of aging in the brain, however, this remains to be shown in simple gangliosides GM2 and GM3. In this study, Matrix-assisted laser desorption/ionization Imaging Mass Spectrometry (MALDI IMS) was used to examine the neuroanatomical distribution of A-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1) in Fisher 344 rats across the lifespan. The ratio of d20:1/d18:1 species was determined across 11 regions of interest in the brain. Interestingly, a decrease in the d20:1/d18:1 ratio for GM2 and GM3 was observed during early development with the exception of the peri-ventricular corpus callosum, where an age-dependent increase was observed for ganglioside GM3. An age-dependent increase in d20:1 species was confirmed for complex gangliosides GM1 and GD1 with the most significant increase during early development and a high degree of anatomical heterogeneity during aging. The unique neuroanatomically-specific responses of d20:1 ganglioside abundance may lead to a better understanding of regional vulnerability to damage in the aging brain.