Linda S. Higgins

Specific spatial learning deficits become severe with age in β-amyloid precursor protein transgenic mice that harbor diffuse β-amyloid deposits but do not form plaques

Memory impairment progressing to dementia is the main clinical symptom of Alzheimers disease (AD). AD is characterized histologically by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles in specific brain regions. Although Aβ derived from the Aβ precursor protein (β-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and/or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human wild-type β-APP751 isoform in neurons. These transgenic mice recapitulate early histopathological features of AD and form Aβ deposits but no plaques. Here we describe a specific and progressive learning and memory impairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant differences in acquisition in 3-month-old mice that increased in severity with age and were expressed clearly in 6-month- and 2-year-old animals. The second transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of training in young but not in aged transgenic animals. Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal β-APP751 transgene-induced memory impairment, which may be caused by β-APP overexpression, isoform misexpression, or elevated soluble Aβ.

β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation

β-amyloid (Aβ), derived form the β-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimers disease (AD), which is characterized by progressive decline of cognitive functions, formation of Aβ plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8- and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.

Expression of Human Apolipoprotein E Downregulates Amyloid Precursor Protein–Induced Ischemic Susceptibility

Background and Purpose— Epidemiological findings and experimental data on transgenic mice show that Alzheimer’s disease–related changes render the brain more susceptible to ischemic damage. We studied whether the previously observed vulnerability in mice overexpressing the 751–amino-acid isoform of human amyloid precursor protein (APP751) is regulated by human apolipoprotein E (apoE) alleles, which determine the relative risk for Alzheimer’s disease and the susceptibility to various forms of acute brain damage. Methods— Aged apoE knock out (KO) mice, mice overexpressing APP751 in the apoE KO background and mice expressing either human apoE3 or apoE4 and APP751 in the apoE KO background were exposed to permanent occlusion of the middle cerebral artery (MCA). Infarct volumes were quantified from T2-weighted magnetic resonance images 24 hours after the MCA occlusion. Local cortical blood flow was monitored by laser Doppler flowmetry. Ischemia-induced microgliosis was detected by immunohistochemistry. Results— Overexpression of human APP751 significantly increased the infarct volumes in apoE KO mice. Furthermore, this APP751-induced ischemic vulnerability was attenuated by the coexpression of either human apoE isoform. MCA occlusion resulted in a similar relative reduction in cortical blood flow in all mouse groups. Vascular anatomy showed no variation in the MCA territory between the groups. Instead, the expression of human apoE isoforms reduced the ischemia-induced microgliosis. Conclusions— Expression of either the human apoE3 or apoE4 isoform protects against the increased ischemic vulnerability observed in aged mice overexpressing human APP751, probably by modulating the inflammatory response induced by MCA occlusion.

Transgenic mice and modeling Alzheimer's disease.

The etiology of Alzheimers disease (AD) is poorly understood, and no effective therapies are available. Although histopathology of the disease has been studied thoroughly, the relationship of various AD lesions to pathological processes and to dementia are debated. Progress would be greatly enhanced by existence of manipulable small animal models of the disease. Recently, transgenic strategies to developing such a model have been extensively explored. The approach has proved to be difficult and has yielded some disappointments, but also some encouraging results. Transgenic strategies for obtaining a model for AD are surveyed in this review and, as an illustration, early AD-like features of transgenic mice produced in our laboratory are described.

β-App-751 Transgenic Mice: Deficits in Learning and Memory

While the etiology of Alzheimer’s disease (AD) is unknown, one of the primary histopathological features of the disease is the accumulation in brain of extracellular deposits of the peptide s-amyloid (s-A4). This peptide is produced by the proteolytic processing of the larger precursor protein s-amyloid precursor protein (s-APP).

Transgenic Mice as a Model of Alzheimer’s Disease

A significant obstacle to determining the role of s-amyloid in Alzheimer’s disease (AD) has been the lack of a manipulable small animal model. The amyloid plaque has been viewed as a major etiological factor in AD dementia and, alternatively, as an epiphenomenon. Transgenic technology provides the potential of a small animal model in which such questions might be addressed experimentally, and which would also be useful in therapeutic development.