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

The aging of the endocrine pancreas of the rat. I. Parameters of cell proliferation.

Morphometrical analysis of the endocrine pancreas of senile 30-month-old rats revealed that the volume density as well as the numeric density of islets of Langerhans were much lower than in 24-month-old rats, which coincided with a much higher percentage of pycnotic nuclei in islet cells. The proportion and localization of the different categories of endocrine cells (A, B, D and PP) remained however unchanged with aging. The apparent problem of cell renewal observed in vivo in the very old age was detected earlier in vitro by tritiated thymidine incorporation. Such experiments showed that 24-month-old islet cells had a decreased labelling index when compared to 3-month-old cells. The proliferation capacity of the old cells could be partially increased by changing the serum concentration or type. Similarly as being more sensitive to serum factors, these cells underwent also more pronounced negative influence of high oxygen pressure on replication. A stereological analysis of the ultrastructure of non-degenerated B-cell nuclei revealed that with age, the relative volume of the condensed chromatin increased progressively at the expense of the dispersed form. This suggests that the still functioning senile B-cells could reduce their transcriptional activity

The aging of the endocrine pancreas of the rat. II. Cytoplasmic parameters of the B-cell, including insulin synthesis and secretion.

Comparative ultrastructural stereology of 6 and 24-month-old rat B-cell cytoplasm revealed an increase with age in secondary lysosomes and a decrease in the volume density of RER and Golgi apparatus. The reduction of RER observed in freshly isolated islets could affect (pro)insulin biosynthesis in vitro: if the initial mobilization of precursor molecules for protein synthesis was the same, a delay was noted in their transit to the Golgi apparatus in B-cells of old islets. No further differences were seen in the autoradiographic distribution of radioactive amino-acids. More, the stock of insulin granules was similar in all age groups in both in vivo and in vitro conditions. Neither were any differences observed in the insulin secretion into culture media as well as during a subsequent incubation in supraphysiological glucose concentrations

The Aging of the Endocrine Pancreas of the Rat .2. Cytoplasmic Parameters of the B-cell, Including Insulin Synthesis and Secretion

Comparative ultrastructural stereology of 6 and 24-month-old rat B-cell cytoplasm revealed an increase with age in secondary lysosomes and a decrease in the volume density of RER and Golgi apparatus. The reduction of RER observed in freshly isolated islets could affect (pro)insulin biosynthesis in vitro: if the initial mobilization of precursor molecules for protein synthesis was the same, a delay was noted in their transit to the Golgi apparatus in B-cells of old islets. No further differences were seen in the autoradiographic distribution of radioactive amino-acids. More, the stock of insulin granules was similar in all age groups in both in vivo and in vitro conditions. Neither were any differences observed in the insulin secretion into culture media as well as during a subsequent incubation in supraphysiological glucose concentrations

The Aging of the Endocrine Pancreas of the Rat .1. Parameters of Cell-proliferation

Morphometrical analysis of the endocrine pancreas of senile 30-month-old rats revealed that the volume density as well as the numeric density of islets of Langerhans were much lower than in 24-month-old rats, which coincided with a much higher percentage of pycnotic nuclei in islet cells. The proportion and localization of the different categories of endocrine cells (A, B, D and PP) remained however unchanged with aging. The apparent problem of cell renewal observed in vivo in the very old age was detected earlier in vitro by tritiated thymidine incorporation. Such experiments showed that 24-month-old islet cells had a decreased labelling index when compared to 3-month-old cells. The proliferation capacity of the old cells could be partially increased by changing the serum concentration or type. Similarly as being more sensitive to serum factors, these cells underwent also more pronounced negative influence of high oxygen pressure on replication. A stereological analysis of the ultrastructure of non-degenerated B-cell nuclei revealed that with age, the relative volume of the condensed chromatin increased progressively at the expense of the dispersed form. This suggests that the still functioning senile B-cells could reduce their transcriptional activity