apoE4 Targeted Replacement Mice Research Articles

A Novel apoE-Derived Therapeutic Reduces Vasospasm and Improves Outcome in a Murine Model of Subarachnoid Hemorrhage

Recent clinical observations demonstrate that the APOE4 genotype increases the development of delayed ischemic deficit and worsens prognosis following aneurysmal subarachnoid hemorrhage (SAH). In the current study, we use targeted replacement mice expressing only human apoE3 or apoE4 to model the isoform-specific effects of apoE following SAH. We then test the hypothesis that an apoE-derived therapeutic peptide reduces vasospasm and improves functional recovery after SAH. Experimental SAH was induced in APOE3- and APOE4-targeted replacement mice. For 3 days following injury, daily functional assessments were made. Mice were then sacrificed and the cerebral vasculature visualized to quantify vasospasm. In a separate experiment, C57Bl/6 mice were treated with intravenous injection of vehicle, low-dose, or high-dose apoE-mimetic peptide every 12 hours for 3 days post-SAH. Functional endpoints were assessed on a daily basis, followed by measurement of middle cerebral artery diameter. Mice expressing the apoE4 isoform had greater functional deficit, mortality, cerebral edema, and vasospasm as compared with their apoE3 counterparts. Mice treated with the apoE-mimetic peptide had decreased mortality, functional deficits, and histological evidence of vasospasm as compared with vehicle-treated animals. Consistent with the clinical literature, the apoE4 isoform is associated with an increased incidence of vasospasm and poor functional recovery after experimental SAH. An apoE-derived peptide represents a novel therapeutic approach for the treatment of SAH.

Blockade of nicotinic acetylcholine receptors suppresses hippocampal long‐term potentiation in wild‐type but not ApoE4 targeted replacement mice

Both impaired nicotinic neurotransmission and the inheritance of apoE4 are associated with increased risk for Alzheimer disease (AD) as well as other deficiencies in memory-related behavior. Long-term potentiation (LTP), a cellular model of memory, is known to be altered by nicotinic agents. Recent studies also support an emergent role for apoE in LTP. We compared the effects of mecamylamine, a nonspecific antagonist of nicotinic acetylcholine receptors (nAChRs), on basal synaptic transmission and LTP in hippocampal slices from wild-type (wt) mice and targeted replacement mice expressing human apoE4 (apoE4-TR). Field excitatory postsynaptic potentials (EPSPs) were recorded in the dentate gyrus (DG) in response to medial perforant path activation, and theta burst stimulation was used to induce LTP. Bath application of mecamylamine (3 microM) did not alter input-output relationships or paired pulse depression in either mouse strain. Under control conditions, apoE4-TR mice showed significantly less LTP than wt mice (17.5% +/- 3.2%, n = 9, vs. 30.1% +/- 3.9%, n = 11, P < 0.02). Mecamylamine reduced LTP in wt mice to a level that was similar to control levels for apoE4-TR mice (15.7% +/- 3.4%, n = 9), whereas apoE4-TR showed no further reduction of LTP (16.6% +/- 3.7%, n = 8) by mecamylamine. Thus mice expressing human apoE4 differ from wt mice both in their capacity for LTP and in the effect on LTP of nicotinic cholinergic blockade. It is possible that nicotinic neurotransmission is already compromised in apoE4-TR mice and, hence, that interference with the integrity of this cholinergic system represents a mechanism by which inheritance of the apoE4 allele contributes to cognitive risk.

Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology

The human APOE*4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE*4 carriers. We examined neurons in the lateral amygdala of young apolipoprotein (apo) E3 and apoE4 targeted replacement (TR) mice for changes in synaptic integrity. ApoE4 mice displayed significantly reduced excitatory synaptic transmission and dendritic arborization. Despite these changes there were no signs of gliosis, amyloid deposition or neurofibrillary tangles in these mice. To our knowledge, this is the first study to suggest that cognitive deficits in APOE*4 carriers are due to inherent defects in synaptic function that appear prior to any age-dependent markers of neuropathology.

Sex steroids, APOE genotype and the innate immune system

Microglia are a primary cellular component of the CNS innate immune system. Their response to conserved pathogen motifs is inherent and leads to the release of cytoactive factors that impact surrounding neurons and glia. The microglial response is modified by the local tissue environment and by “global” factors such as gender. Exposure to estrogen and testosterone, in general, down regulate microglia and peripheral macrophage function, promoting an anti-inflammatory phenotype. Other global factors, however, can “override” the gender-based effects demonstrated by estrogen or testosterone. Apolipoprotein E (APOE) genotype and the expression of specific isoforms of apolipoprotein E differentially regulate microglial and peripheral macrophage function. Our studies have shown that the presence of the APOE4 gene, a known risk factor for AD and other neurodegenerative diseases, promotes a pro-inflammatory macrophage phenotype in neonatal microglia. However, in adult mice, the APOE genotype-specific effect depends on gender. Peritoneal macrophages from female adult APOE3 and APOE4 targeted replacement mice do not demonstrate an APOE genotype-specific response, whereas adult male APOE4 targeted replacement mice show enhanced macrophage responsiveness compared to adult male APOE3 mice. At least part of the altered macrophage response in APOE4 male mice may be due to differences in androgen receptor sensitivity to testosterone. These data re-enforce the concept that classical activation in macrophages has multiple levels of regulation, dictated by competing or synergistic factors and genotype.

P2-298 Effects of a high fat diet on brain lipid levels in human apoE targeted replacement mice

P2-298 Effects of a high fat diet on brain lipid levels in human apoE targeted replacement mice

APOE genotype-specific differences in human and mouse macrophage nitric oxide production

Individuals expressing an APOE4 genotype demonstrate increased Alzheimer's disease (AD) neuropathology and a decreased onset age. The APOE4 gene may act by modulating the CNS immune response. Using human monocyte-derived macrophages (MDM), we show a significantly greater increase in NO production during immune activation in MDM from APOE4 AD patients compared to normal, age-matched individuals or to AD patients with an APOE 3/3 genotype. Microglia and peritoneal macrophages from APOE4 targeted replacement mice demonstrate a similar increase in NO compared to the APOE3 targeted replacement mice. The enhanced macrophage responsiveness and the increased production of NO in APOE4 AD patients may predispose the CNS to an increased potential for nitration and nitrosation, consistent with the redox imbalance and neuroinflammatory state seen in AD.

Ventromedial temporal lobe anatomy, with comments on Alzheimer's disease and temporal injury.

The ventromedial temporal area has a complicated topography and neuroanatomy that has yielded secrets only grudgingly. The major features of surface topography are reviewed here as well as recent neuroanatomical findings that establish the ventromedial temporal area as both a recipient of cortical input and the origin for widespread output back to the cortex. The devastating involvement of all ventromedial temporal areas in Alzheimer's disease is highlighted, and comments are offered on the tentorium cerebelli and on mechanical injury to the area.