Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimer's Disease

Abstract

BackgroundTransgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral β-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.Methodology/Principal FindingsThe transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APPswe) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral β-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a γ-secretase inhibitor we show a dose dependent reduction of soluble amyloid β levels in the brain.ConclusionsARTE10 mice develop a cerebral β-amyloidosis closely resembling the β-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD.

FBL2 Regulates Amyloid Precursor Protein (APP) Metabolism by Promoting Ubiquitination-Dependent APP Degradation and Inhibition of APP Endocytosis

“…FBL2 overexpression was also expected to reduce the amount of APP in vivo. However, the effect of FBL2 on APP protein levels was unclear in AD1/FBL2 transgenic mice (referred to as ARTE10 by Willuweit et al, 2009), because of high APP expression levels that could preclude detection of changes in the amount of APP. However, we did confirm that APP ubiquitination was increased in AD1/FBL2 transgenic mice.…”

“…Double-transgenic AD1 mice, harboring Thy1.2 promoter-driven human APP SW and human PS1 M146V stably coinherited transgenes in a C57BL/6 background, were generated by Artemis Pharmaceuticals (referred to as ARTE10; Willuweit et al, 2009). To investigate FBL2 function in APP/A␤ metabolism in vivo, hFBL2 transgenic mice harboring Thy1.2-human FBL2 (hFBL2) in Rosa locus were crossed with AD1 mice.…”

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

“…Increased expression of human APP in rodents (Chishti et al 2001;Freude et al 2009;Hsiao et al 1995;Moechars et al 1999;Willuweit et al 2009), flies (Greeve et al 2004;Rajendran et al 2008), or humans is associated with premature mortality and an Alzheimer-like pathology (Isacson et al 2002;Rovelet-Lecrux et al 2006;Sleegers et al 2006;Wisniewski et al 1985). There have been numerous reports in mice showing that overexpression of human APP or mutant human APP leads to increased mortality in young mice even before the onset of visible Alzheimer-like pathology or neurodegeneration (El Khoury et al 2007;Hsiao et al 1995).…”

Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer’s Disease

“…To address this question, we recorded, in parallel, the membrane potential dynamics of single CA1 pyramidal neurons using the whole-cell patch-clamp technique and the hippocampal local field potential (LFP) in isoflurane-anesthetized, double-transgenic APP/PS1 (Willuweit et al, 2009) and age-matched wild-type mice (Figure 1A). These experiments were performed at an age range of 10-14 months, at which these mice exhibit hippocampal amyloid accumulation ( Figure S1 available online) and learning deficits (Willuweit et al, 2009).…”