Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer's disease mouse model

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Abstract
Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to the early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wildtype littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid‐β protein, may underlie the observed neuronal loss. J. Comp. Neurol. 522:2319–2335, 2014.
Funding Information
  • National Institutes of Health (T32 GM062754 (to J.W.S.), F31 AG039890 (to H.B.), P50 AG005138 (to D.L.D., S.G., P.R.H.), P01 AG010491 (to S.G.), R01 AG035071 (to P.R.H., C.M.W.))
  • Canadian Institutes of Health Research (MOP-115056 (to P.E.F.))
  • The Canada Research Chairs
  • Alberta Innovatives-Health Solutions
  • the Alberta Prion Research Institute (to D.W.)
  • Wellcome Trust
  • Medical Research Council
  • The Howard Hughes Medical Institute
  • the Alzheimer Society of Ontario (to P.E.F., P.H.H.)

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