Aging Aging

Genetically Engineered Mice 369mulation of amyloid plaques and neuritic tangles in the cerebral cortex and thehippocampus that eventually leads to the neurodegeneration and resulting cognitivedecline associated with this disorder.APP overexpressing transgenic lines have been constructed in which eithera shorter form of the human APP cDNA containing the same mutation found ina familial Swedish Alzheimer’s pedigree was expressed behind the prion proteinpromoter (PrP) or a longer form of the cDNA containing a separate mutationwas expressed from the platelet-derived growth factor (PDGF) promoter(52,53). In both cases, mice were found to develop the selective amyloidplaques and gliosis in the hippocampus and cortex characteristic of the diseaseby 6 to 12 mo of age. Plaque development appeared to be dependent on whichbackground strain the APP cDNA was expressed in, suggesting the presence ofallelic modifier genes (52). In the Hsiao line, a loss in cognitive ability as exemplifiedby a deficit in various learning and memory tests was also reported,although the loss was somewhat variable (52).Transgenic mice expressing mutant human presenilin-1 (PS-l) cDNA undercontrol of the PDGF promoter exhibited an increase in β-amyloid (Aβ) deposition,a product of abberrant APP processing that is found to be elevated in thebrains of Alzheimer’s disease patients and is considered a hallmark of the disease(54). Amyloid deposits or behavioral deficits have yet to be reported inthese animals. Double transgenics expressing both mutant APP and PS-i cDNAhave an accelerated rate of amyloid deposition (55).An important issue to be addressed with the lines described above is thetemporal relationship between the formation of amyloid deposits and the onsetof memory deficits in these animals (56). If cognitive effects occur prior to Aj3deposition, this would imply that it is the soluble form of Aβ as opposed to thefibrillary form that is responsible for disease pathology and that amyloidplaques may occur coincidentally along with cognitive decline. Interestingly,there appears to be no correlation between the amount of Aβ deposition anddegree of dementia in humans with the disease, and in addition transgenic miceexpressing the Swedish APP mutation in the FVB background show cognitiveeffects in the absence of plaque formation (52,57).8.2. ImmunosenescenceGenetically engineered mice have also been used to study the phenomenonof immunosenescence. Older people have an increased susceptibility to infectionas a result of an age-related decrease in the responsiveness of the immunesystem to attack by foreign antigens such as bacteria and viruses. This immunodeficiencyappears to be primarily due to a decline in the response of T cellsto receptor stimulation which in turn can result in a decline in both T-cell proliferationand alterations in cytokine secretion (58). There appears to be an