In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease

Smith, Karen Dell Brown, et al. "< i> In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease." Neuroimage 35.4 (2007): 1401-1408. Introduction: Primarily, the neurodegenerative disease Alzheimer’s affects a large population of the elderly. The disease presents itself with cognitive pathologies that correspond to intracellular neurofibrillary tangles (NFT’s) and extracellular amyloid-β aggregations (plaques) that eventually lead to neural death. Previous research has shown that another factor that contributes to cell death is a decrease in axonal transport rates, mostly in fast response neurons. Presently, it is unknown if the aggregation of tau proteins within NFT’s or an increase in amyloid precursor protein that precede plaques are causative of slowing axonal transport rates or consequential. This study utilizes the novel in vivo technique manganese-enhanced MRI (MeMRI), to try and gain knowledge on the decrease in axonal transport rates within Alzheimer modeling rodents. Methods: • Mn2+ Administration: MnCl2 (4l of .75 mg/ml) was given via a nasal lavage. • MeMRI: Animals were imaged an hour prior to MnCl2 injection using a 9.5T Bruker Avance Biospec Spectrometer. • Colchicine Administration: Colchine (1mg/kg) was given via a nasal lavage 24hrs prior to Mn2+ injection. • Immunoblotting: for APP concentration • Immunohistochemistry: for plaque detection Conclusion: • 3-4 month old rats did not reveal any signs of soluble APP or plaque presentation. 7-8 month old rats exhibited significant increases in soluble APP, but no plaques were identified. Finally 11-14 month old rats revealed both increases in soluble APP as well as plaque formation. • MeMRI revealed that following a normal temperature of 37 degrees Celsius, a drop in temperature to 30 degrees Celsius significantly reduces changes in signal intensities over time (axonal transport rate of Mn2+). It also showed that if temperatures were restored to physiological body temperatures following hypothermia, Mn2+ transport regained normal function and transport rates returned to baseline. This experiment showed that using MnCl2 a neuronal tract tracer can also be used for functional analysis of axonal transport rates, not just structural identification. • It was then determined that after the administration of Colchine, that microtubule depolymerization can be achieved, as well as the block in axonal Mn2+ transport. This study was able to show the dependence of Mn2+ transport on microtubule axonal transport and that manganese intensity analysis is a valid quantification of axonal transport rates. • After conformation, both Alzheimer’s disease (AD) model rodents and control rodents were imaged at three different time points: 3-4 months, 7-8 months, and 11-14 months old. As discussed earlier, each time point representing a different state of disease progression. The study concluded that at months 3 and 4 axonal transport of Mn2+ did not differ from control rats. However, at 7-8 months there was a significant decrease in transport rates when compared to control rats. Finally, again at 11-14 months a further significant decrease from baseline was seen in AD models compared to the control rats. This finding is important in showing that axonal transports rates begin to decrease before the formation of plaques are identified, which has never been shown. One possible explanation for this finding is that the soluble APP is interfering with Ca2+ influx rates, slowing down transport. ~JI