Transgenic expression of intraneuronal Aβ42 but not Aβ40 leads to cellular Aβ lesions, degeneration, and functional impairment without typical Alzheimer's disease pathology.

Abstract

An early role of amyloid-beta peptide (Abeta) aggregation in Alzheimer’s disease pathogenesis is well established. However, the contribution of intracellular or extracellular forms of Abeta to the neurodegenerative process is a subject of considerable debate. We here describe transgenic mice expressing Abeta1– 40 (APP47) and Abeta1– 42 (APP48) with a cleaved signal sequence to insert both peptides during synthesis into the endoplasmic reticulum. Although lower in transgene mRNA, APP48 mice reach a higher brain Abeta concentration. The reduced solubility and increased aggregation of Abeta1– 42 may impair its degradation. APP48 mice develop intracellular Abeta lesions in dendrites and lysosomes. The hippocampal neuron number is reduced already at young age. The brain weight decreases during aging in conjunction with severe white matter atrophy. The mice show a motor impairment. Only very few Abeta1– 40 lesions are found in APP47 mice. Neither APP47 nor APP48 nor the bigenic mice develop extracellular amyloid plaques. While intracellular membrane expression of Abeta1– 42 in APP48 mice does not lead to the AD-typical lesions,A aggregates develop within cells accompanied by considerable neurodegeneration.