Alzheimer disease models and human neuropathology: similarities and differences

Abstract

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 Abeta peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Abeta peptide, similar but not identical to the Abeta peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Abeta, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Abeta 42 levels, except for the Arctic mutation, which alters the Abeta sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Abeta 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 Abeta. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Abeta 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 Abeta 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 Abeta 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.

Fig. 1a–b

Connections of plaques. a The anterograde tracer biotinylated dextran amine (BDA) was injected into the mediodorsal nucleus of the thalamus. The prefrontal cortex was examined after Congo red staining. The anterogradely labeled fibers are shown in brown (long arrow). The normal connections are present and avoid the plaque, whose core is stained by Congo red (small arrow). b BDA was injected into the posterior cingulate cortex. Labeled fibers are visible in the visual cortex (black), which is normally connected with the posterior cingulate cortex. Several fibers (arrows) come into contact with the amyloid deposit (brown; immunolabeled by a polyclonal anti-Aβ42 antibody) and appear dystrophic. Bar = 10 μm for a and b. This experiment suggests that only a subset of the cortical connections “innervates” the plaque [75]

Fig. 2

Comparison of extracellular deposition and intracellular accumulation of Aβ peptide in APPxPS1 Tg Mice. Five illustrative mice, taken at 2, 5, 9, 11, and 15 months of age, were studied. Sections, 25 μm in thickness, were immunostained with an anti-Aβ_8–17 antibody (clone 6F/D3; Dako, Glostrup). The extracellular deposits of Aβ peptide are plotted on the left side in green; the intracellular granules of Aβ peptide are shown in red on the right side. Intracellular Aβ is visible after just two months, before the appearance of extracellular deposits. The density of intracellular Aβ decreases with the increase in the density of extracellular deposits of Aβ peptide. Scale bar = 1 mm. Modified from [186]