توسعه تغییر یافته مغزی در مدل موش بیماری زودرس آلزایمر

Murine models of Alzheimer's disease (AD) have been used to draw associations between atrophy of neural tissue and underlying pathology. In this study, the early-onset TgCRND8 mouse model of AD and littermate controls were scanned longitudinally with in vivo manganese-enhanced MRI (MEMRI) before and after the onset of amyloid plaque deposition at 12 weeks of age. Separate cohorts of mice were scanned at 1 week (ex vivo imaging) and 4 weeks (MEMRI) of age to investigate early life alterations in the brain. Contrary to our expectations, differences in neuroanatomy were found in early post-natal life, preceding plaque deposition by as much as 11 weeks. Many of these differences remained at all imaging time points, suggesting that they were programmed early in life and were unaffected by the onset of pathology. Furthermore, rather than showing atrophy, many regions of the TgCRND8 brain grew at a faster rate compared to controls. These regions contained the greatest density of amyloid plaques and reactive astrocytes. Our findings suggest that pathological processes as well as an alteration in brain development influence the TgCRND8 neuroanatomy throughout the lifespan.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive impairments, dementia, and eventual death. The decline in cognitive function has been attributed to a cascade of neuropathology that alters the cellular and molecular environment in the brain. Early in the disease, toxic soluble amyloid-β (Aβ) oligomers disrupt the structure and function of neuronal synapses (Ferreira and Klein, 2011 and Lacor et al., 2007). As the amyloid burden increases, these soluble fragments deposit as insoluble plaques in the parenchyma (Braak and Braak, 1991) and around the vasculature (Zlokovic, 2005), triggering an inflammatory response (Wyss-Coray, 2006). By the late stages, accumulations of intracellular neurofibrillary tangles impair cellular function and contribute to neuronal death (Braak and Braak, 1991). These pathological events cumulatively change the anatomy of the brain (Lehéricy et al., 2007). In particular, the atrophy of cortical and hippocampal regions has been correlated with cognitive decline and can be used as an early diagnostic tool to differentiate AD progression from mild cognitive impairment (Apostolova and Thompson, 2008, Chételat et al., 2010 and Mcevoy et al., 2009). Thus, monitoring the neuroanatomical changes in AD and the relationship to the underlying neuropathology is important for advancing our understanding of disease progression and for developing treatments that target the cellular mechanisms of atrophy. Mouse models of AD offer the opportunity to directly study the relationship between the pathological processes of the disease and the effects on brain anatomy. Previous cross-sectional and longitudinal magnetic resonance imaging (MRI) studies of murine models of AD have demonstrated that regional and whole-brain anatomical changes arise as the pathological burden develops (Badea et al., 2010, Delatour et al., 2006, Grand’maison et al., 2013, Hébert et al., 2012, Maheswaran et al., 2009 and Redwine et al., 2003). However, many of these studies have limited their analyses to a few time points before or after the onset of AD plaque deposition, potentially overlooking important spatial and temporal information. To study the relationship between the cellular mechanisms of disease and the corresponding changes in neuroanatomy, multiple imaging sessions must be implemented before and after the onset of AD pathology. We set out to longitudinally track the MRI-detectable neuroanatomical changes over the time course of pathology using the early-onset TgCRND8 mouse model of AD. In this model, Aβ plaque deposition arises in the cortex and hippocampus by 12 weeks of age, followed by reactive micro- and astrogliosis, dystrophic neuropathy, decreased spine density, and vascular impairments (Chishti et al., 2001, Dorr et al., 2012, Dudal et al., 2004, Steele et al., 2014 and Woodhouse et al., 2009). In this study, TgCRND8 and wild-type littermate control mice were imaged with MRI before (9 weeks of age) and on multiple occasions after the reported onset of plaque deposition (12, 16, and 20 weeks of age). These intervals between scanning sessions were chosen to acquire a precise time course of the neuroanatomical changes, as the TgCRND8 quickly becomes affected by pathology around 12 weeks of age (Chishti et al., 2001). Based on the previously characterized disease progression, we hypothesized that alterations in the TgCRND8 brain would correspond to the timing of plaque deposition, with no apparent differences before this event and substantial volume changes as the pathological burden increased. We further hypothesized that degenerative mechanisms, such as reduced synaptic density, would drive decreases in brain volume, whereas the accumulation of plaques and reactive astrogliosis would displace the surrounding parenchyma, ultimately leading to volume increases. We initiated the study by longitudinally imaging mice over the time course of amyloid plaque deposition (9, 12, 16 and 20 weeks of age) with the intention of monitoring the relationship between brain atrophy and disease progression. Rather than atrophying, regions of the TgCRND8 brain grew at a faster rate compared to those of controls. However, of particular interest were the unexpected differences in neuroanatomy before the onset of plaque deposition. These findings motivated us to scan separate cohorts of mice at 1 week and 4 weeks of age to determine when the neuroanatomy began to diverge between groups. Interestingly, neuroanatomical differences were apparent at these early post-natal time points and were localized to brain regions similar to those of the older mice in the longitudinal study. These findings led us to conclude that the TgCRND8 is affected by an alteration in brain development that persists into adulthood.

Monitoring mice longitudinally allowed examination of the spatial and temporal dynamics of neuroanatomical changes over the time course of AD-related pathology development, highlighting the strength of whole-brain longitudinal MRI studies. Previous MRI studies in AD mice have suggested that the differences in the brain anatomy may somehow be associated with a developmental process (Delatour et al., 2006, Lau et al., 2008 and Redwine et al., 2003). Our study demonstrates that many regional volume differences between TG and WT are apparent at 1 week of age and remain throughout adulthood. These findings strongly suggest that the TgCRND8 is not solely a murine model of AD but, rather, a model of amyloid plaque deposition and related pathology, compounded by a neurodevelopmental phenotype. Contemporary treatments for Alzheimer's disease attempt to delay synaptic loss and brain atrophy associated with cognitive decline early in the disease. To properly test prevention-focused interventions in mice, experimentation would need to begin early before the onset of pathology. Our study demonstrates that the developmental alterations in the brain of the TgCRND8 mouse model of AD need to be accounted for when testing these early-life interventions.