![]() ![]() ![]() Amyloid-β accumulating in the brains of APP Tg mice is neither physically, chemically or functionally equivalent to that characteristic of human AD. While Aβ plays a central pathologic role, Tg mice affirm that AD entails more than alterations in APP/Aβ overproduction, clearance and deposition. ![]() Finally, immuno-responsive AD patients vaccinated against Aβ42 showed substantial clearance of amyloid plaques from the gray matter, without concomitant dementia abrogation. Fourth, it is well accepted that SAD is multifactorial and pleiotropic in its pathological and clinical manifestations and that these interactions are strongly influenced by risk factors such as apolipoprotein E (ApoE) genotype, cardiovascular pathology and disturbances in lipid and glucose metabolism. More important, these features are widely seen in aged, non-demented (ND) individuals. Third, both Aβ and tau accumulation are observed in other neurodegenerative disorders. Second, no specific mutations in the Aβ peptide explain the massive pathological amyloid deposition in the most common sporadic form of AD. First, Tg mice reproduction of AD pathology is based on the transfection of mutant APP, PS and tau genes, alone or in combination, that reproduce only some of the pathological changes seen in FAD. The preeminence of the amyloid cascade hypothesis as a unique pathogenic factor in sporadic AD (SAD) is being re-examined as a consequence. The reproduction of these pathological alterations in APP and presenilin (PS) Tg mice added a powerful confirmation to the “amyloid cascade hypothesis”, but although sophisticated mouse models have been created, none faithfully recapitulate the extensive cellular, biochemical and behavioral pathology of AD patients. A major step toward the exploration of AD pathophysiology and the evaluation of potential treatments was the creation of transgenic (Tg) mice with gross amyloid deposition due to over-expression of human familial Alzheimer’s disease (FAD) amyloid precursor protein (APP) mutations. ![]() Accumulating toxic forms of Aβ disrupt neuronal and glial homeostasis and destroy brain and cerebrovascular tissue architecture. These observations suggest that the pathogenesis of AD is by far much more intricate than the straightforward accumulation of Aβ.Īmyloid-beta (Aβ deposition combined with neurofibrillary tangles (NFT), are important pathological features of Alzheimer’s disease (AD). The disparity between success and failure is in part due to differences in brain environment that separate man and rodent. Unfortunately, clinical trials resulted in unforeseen adverse events or negative therapeutic outcomes. Tg mice have been widely used for testing AD therapeutic agents and demonstrated promising results. The greater resilience of Tg mice to substantial Aβ burdens suggests the levels and forms that are deleterious to human neurons are not as noxious in these models. The morphological resemblance to AD amyloidosis is impressive, but fundamental biophysical and biochemical properties of the APP/Aβ produced in Tg mice differ substantially from those of humans. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. Transgenic (Tg) mice overexpressing mutant familial Alzheimer’s disease (AD) amyloid precursor protein (APP) genes have contributed to the understanding of dementia pathology and support the amyloid cascade hypothesis. ![]()
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