Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein

Abstract

Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

APP mouse models for Alzheimer's disease preclinical studies

“…Frequently used models include PDAPP (Games et al , 1995), Tg2576 (Hsiao et al , 1996), APP23 (Sturchler‐Pierrat et al , 1997), J20 (Mucke et al , 2000), and TgCRND8 (Chishti et al , 2001). The APP constructs differ among the lines: They include APP695, APP770, and minigenes.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…These transgenic mice produce high levels of human Ab40 and Ab42 peptides and develop amyloid deposits in the brain which are very similar to those seen in the human AD brain and thus represent a unique tool in the study of this condition. The first animal models that developed amyloid plaques were generated by integrating in the mouse genome the gene encoding human APP containing mutations associated with early-onset AD ( [76,101,215]). These mice develop amyloid plaque pathology and selective cognitive deficits, pathologic features that dramatically accelerate in the next generation of AD animal models generated by crossing APP mutant animals with mice carrying the mutated PSEN1 gene ( [20,63,98]).…”

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

“…This could explain the virtual absence of Aβ deposits in normal young and aged rodent brains. Therefore, transgenic models of Aβ pathology have been developed that overexpress human APP (hAPP) with AD‐associated mutations which favour the amyloidogenic β‐secretase pathway of APP processing (Games et al ., 1995; Hsiao et al ., 1996; Sturchler‐Pierrat et al ., 1997). These mice have been used to test therapeutic strategies that aim at reducing Aβ generation, for example by treatment with β‐secretase inhibitors and by active and passive immunization approaches (Solomon et al ., 1996; Schenk et al ., 1999; Eketjall et al ., 2013).…”