Alzheimer disease models and human neuropathology: similarities and differences

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of A beta peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of A beta peptide, similar but not identical to the A beta peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of A beta, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in A beta 42 levels, except for the Arctic mutation, which alters the A beta sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no A beta deposition in most mouse lines. Doubly (APP x mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of A beta. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of A beta in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in A beta oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau -/- background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of A beta or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis.