In vivo characterization of a bigenic fluorescent mouse model of Alzheimer's disease with neurodegeneration

Abstract

The loss of cognitive function in Alzheimer’s disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing “H-line” yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12–14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention.

In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques

“…Otherwise a decline in growth would be expected due to the ever-increasing surface area of β-amyloid plaques which requires a proportional increase in the amount of Aβ to maintain a constant linear growth rate. A comparison of plaque growth of the Tg2576 with the APPPS1 mouse model that was investigated by two other studies, using exactly the same methods and data analysis, supports this hypothetical assumption [16-20,31]. Although APPPS1 mice produce much more Aβ and accumulation starts much earlier than in Tg2576 mice [9,19,23,30] median plaque growth rates were about 0.3 μm/week in both mouse models [16-20,31].…”

Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice

“…Specifically, we detected a decrease in spontaneous miniature excitatory post-synaptic currents (mEPSCs) frequency and amplitude, higher threshold for firing of action potentials, a decrease in spike half-width duration and a decrease in synaptic weight following spike-timing dependent plasticity (STDP). We have recently shown that spine density and morphology on layer 5 neurons in young 5xFAD mice are unchaged from age-matched controls (Crowe and Ellis-Davies, 2013b), our data suggest that these cells in the 5xFAD mouse model undergo synaptic deficits at an early time point, before any overt structural dystrophy (Crowe and Ellis-Davies 2013a), and that such synaptic failure, with co-temporal biochemical changes(Eimer and Vassar, 2013), may be an early step in neuronal loss.…”

“…More recent quantitative analyses of such decay revealed that between 25%(Eimer and Vassar, 2013) to 38%(Jawhar et al ., 2012) of layer 5 neurons are lost by 12 months of age. Furthermore, we have shown recently by high-resolution imaging in vivo and in vitro that dendritic spines are stable at 4 months of age, whilst axons are starting to show signs of dystrophy at this time(Crowe and Ellis-Davies, 2013a). Since the 5xFAD mouse is one of the few amyloid transgenic mice to exhibit profound structural decay, it has attracted considerable interest from several research groups.…”

“…Recently, Vassar and coworkers have developed a new transgenic murine model with five FAD mutations (called the “5xFAD” mouse) and they reported that this FAD mouse model had significant neuronal loss of layer 5 pyramidal neurons(Oakley et al ., 2006). This striking feature has lead to many studies of this new FAD mouse addressing various aspects of the mouse as a disease model, including behavioral tests(Kaczorowski et al ., 2011), hippocampal long-term potentiation(Kimura and Ohno, 2009, Kimura et al, 2010, Kaczorowski et al, 2011), neuronal atrophy(Crowe and Ellis-Davies, 2013a, b), and biochemical analyses(Zhao et al, 2007, O’Connor et al, 2008, Zhang et al, 2009, Wirths et al, 2010, Youmans et al, 2011). …”

Can BACE1 Inhibition Mitigate Early Axonal Pathology in Neurological Diseases?

“…BACE1 elevation appears to occur in the brain from a fairly early age among several plaque-forming transgenic AD models examined so far, including Tg2576, 2XFAD, 5XFAD, and 3xTgAD [10,11,35-37,39,66,67]. Importantly, the onset and evolution of typical neuritic plaques in the brain and spinal cord correlate with a progressive axon terminal pathology associated with BACE1 overexpression.…”