Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease

Abstract

Transgenic mice carrying disease-linked forms of genes associated with Alzheimer disease often demonstrate deposition of the β-amyloid as senile plaques and cerebral amyloid angiopathy. We have characterized the natural history of β-amyloid deposition in APPswe/PS1dE9 mice, a particularly aggressive transgenic mouse model generated with mutant transgenes for APP (APPswe: KM594/5NL) and PS1 (dE9: deletion of exon 9). Ex vivo histochemistry showed Aβ deposition by 4 months with a progressive increase in plaque number up to 12 months and a similar increase of Aβ levels. In vivo multiphoton microscopy at weekly intervals showed increasing β-amyloid deposition as CAA and plaques. Although first appearing at an early age, CAA progressed at a significantly slower rate than in the Tg2576 mice. The consistent and early onset of β-amyloid accumulation in the APPswe/PS1dE9 model confirms its utility for studies of biochemical and pathological mechanisms underlying β-amyloid deposition, as well as exploring new therapeutic treatments.

Introduction

Dementia is characterized by a progressive memory loss, cognitive deterioration and behavioral disorders. Although there are many causes of dementia, Alzheimer disease (AD) and vascular dementia account for the majority of cases worldwide. AD prevalence tends to double every 5 years after 65, affecting almost 50% of the population over 85 (Evans et al., 1989). With the aging of the population, this has led to escalating health care costs, as well as societal and personal burdens. Senile plaques are a major hallmark of the disease, composed mainly of the 39–43 amino acid peptide amyloid-β (Aβ) (Selkoe, 1998, Selkoe, 2006), derived from proteolytic processing of the transmembrane glycoprotein amyloid precursor protein (APP). Mutations in the genes that encode APP and some components of the proteases that generate Aβ (PS1, PS2) cause familial forms of AD. Another major neuropathologic finding in AD is the presence of neurofibrillary tangles, containing hyperphosphorylated forms of the microtubule-associated protein tau. Mutations in the gene encoding tau are not associated with AD, but rather cause another form of dementia—frontotemporal dementia.

There is also increasing evidence supporting the role of cerebrovascular disease as a contributing factor to dementia (O’Brien et al., 2003). One such cerebrovascular pathology of aging is cerebral amyloid angiopathy (CAA), characterized by extracellular Aβ deposits in the vessel walls, causing vessel wall disruption and eventually parenchymal hemorrhage (Hardy and Cullen, 2006, zhang_Nunes et al., 2006). CAA is present in up to 80% of cases of AD diagnosed at autopsy (Jellinger, 2002, Weller et al., 2000, Weller et al., 2004), suggesting that cerebrovascular disease may be a factor in the failure of elimination of Aβ from the brain in AD, linking aging in cerebral arteries with the pathogenesis of AD (Nicoll et al., 2004).

Different animal models have been developed to study the etiology, evolution and new therapeutic alternatives for the illnesses. Transgenic mouse models have been created with mutations in genes related to AD and CAA (Spires and Hyman, 2005), including APP (Hsiao et al., 1996), apolipoprotein E (APOE) (Raber et al., 1998), presenilin 1 (PS1) (Mehta et al., 1998) or presenilin 2 (PS2) (Herreman et al., 1999). Moreover, double transgenics, such as PS1/APP (Holcomb et al., 1998) or PS2/APP (Richards et al., 2003), have been demonstrated to have accelerated development of pathology relative to single transgenics, facilitating studies that would be difficult in very old and fragile animals. Enhanced neurofibrillary degeneration has been observed in transgenic mice expressing mutant tau and APP (Lewis et al., 2001). Moreover, triple transgenics harboring hPS1(M146V), APP(Swe) and tau (P301L) transgenes provide a valuable model for evaluating the relationships between Aβ, synaptic dysfunction and tangles (Oddo et al., 2003).

Recently, mice harboring both the APPswe and PS1dE9 mutant transgenes have been developed (Jankowsky et al., 2001). This mouse was developed by co-injection into pronuclei of the two transgene constructs [mouse/human (Mo/Hu) chimeric APP695 harboring the Swedish (K594M/N595L) mutation and exon-9-deleted PS1] with a single genomic insertion site resulting in the two transgenes being transmitted as a single mendelian locus. There is reported to be early Aβ deposition in these animals, observed as soon as 4–6 months of age (Jankowsky et al., 2004a), and the animals are available through a commercial source, making them a potentially attractive model system in which to study AD progression and therapeutic modulation. Because the time course of the disease pattern and progression has not been well characterized, we have analyzed the natural history of Aβ deposition in these animals, assessing both senile plaques and CAA evolution.