Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe^−/−Mice: Isoform-Specific Effects on Neurodegeneration

Abstract

Apolipoprotein (apo) E isoforms are key determinants of susceptibility to Alzheimer's disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

“…Young (3-5 months old) Apoe -/-and wild-type mice were used in all the experiments, as indicated (n ¼ 5-19 mice per group). Young Apoe -/-mice were studied to evaluate a potential role of apoE on H 3 -receptor-mediated signaling, as adult Apoe -/-mice show age-dependent structural and functional alterations in the cortex and hippocampus (Masliah et al, 1995;Raber et al, 1998;Buttini et al, 1999). Such alterations could cause secondary changes in H 3 -receptor-mediated signaling.…”

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

“…This method has been validated with quantitative immunoblots and enzyme-linked immunosorbent assays [4,20,21]. Similar procedures were used to quantify Bassoon-positive presynaptic boutons, the area of the neuropil occupied by MAP-2-immunolabeled dendrites, and NLG1-positive postsynaptic sites.…”

Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

“…3,7 We therefore used confocal microscopy of immunolabeled brain sections and computer-aided image analysis to assess the integrity of presynaptic terminals and neuronal dendrites in the different groups of mice. This semiquantitative assessment of neurodegenerative alterations (see Materials and Methods for details) has been used successfully in diverse experimental models 3,24,32 and in diseased human brains. 22,33,34 It has also been validated previously by comparisons with quantitative immunoblots, 35 quantitations of synaptic proteins by enzymelinked immunosorbent assay, 32,36 and modifications of the stereological "disector" approach.…”

“…This semiquantitative assessment of neurodegenerative alterations (see Materials and Methods for details) has been used successfully in diverse experimental models 3,24,32 and in diseased human brains. 22,33,34 It has also been validated previously by comparisons with quantitative immunoblots, 35 quantitations of synaptic proteins by enzymelinked immunosorbent assay, 32,36 and modifications of the stereological "disector" approach. 37 Compared with hAPP Ϫ/Ϫ SR ϩ/ϩ controls, hAPP Ϫ/Ϫ SR Ϫ/Ϫ mice had normal levels of synaptophysin-immunoreactive presynaptic terminals (Figure 5), suggesting that lack of the SR does not by itself result in abnormal central nervous system (CNS) development or neurodegenerative alterations.…”