A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer's Disease

Abstract

Elucidating the age-dependent alterations in transgenic (Tg) mice overexpressing amyloid-β protein precursor (AβPP) is important for understanding the pathogenesis of Alzheimer’s disease (AD) and designing experimental therapies. Cross-studies have previously characterized some time-dependent behavioral and pathological alterations in AβPP Tg mice, however, a more comprehensive longitudinal study is needed to fully examine the progressive nature of behavioral deficits in these mice. In order to better understand the age- and gender-dependent progression of behavioral alterations, we performed a longitudinal study wherein Tg mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the neuron specific murine (m)Thy-1 promoter (mThy1-hAβPP751) were behaviorally analyzed at 3 months and then re-tested at 6 and 9 months of age. The results show that there was an age-associated impairment in learning in the water maze task and habituation in the hole-board task. Motor coordination of the mThy1-hAβPP751 Tg mice was well-preserved throughout the investigated life span however, gender-specific deficits were observed in spontaneous activity and thigmotaxis. Neuropathologically, mThy1-hAβPP751 Tg mice displayed a progressive increase in the number of Aβ plaques and mean plaque size in the cortex and hippocampus from 3 to 6 and from 6 to 9 months of age. Taken together, these results indicate that the mThy1-hAβPP751 Tg mice model AD from the early onset of the disease through to later stages, allowing them to be utilized at numerous points during the timeline for drug test designs.

Influence of Lentiviral β-Synuclein Overexpression in the Hippocampus of a Transgenic Mouse Model of Alzheimer's Disease on Amyloid Precursor Protein Metabolism and Pathology

“…3e). In line with previous reports [39], Aβ deposition increased age dependently in APP SL mice and was expectedly absent in ntg animals (fig. 3d, e).…”

“…These mice overexpress hAPP with Swedish (K670M/N671L) and London (V717I) mutations under the control of the neuron-specific murine Thy1 promoter [39]. Behavioral tests were performed 1, 3 and 6 months after lentiviral injections (at the ages of 7, 9 and 12 months).…”

“…APP SL mice overexpress human APP (hAPP) with Swedish (K670M/N671L) and London (V717I) mutations under the control of the neuron-specific Thy1 promoter [38]. The APP SL mouse line exhibits progressive amyloid pathology mainly in the hippocampus and is associated with early-onset memory decline [39]. The hippocampus represents a brain area that is important for cognition and which is also severely afflicted in the course of AD [40].…”

Detection of Peri-Synaptic Amyloid-β Pyroglutamate Aggregates in Early Stages of Alzheimer's Disease and in AβPP Transgenic Mice Using a Novel Monoclonal Antibody

“…Loss of pre-synaptic terminals and dendritic spines has been shown to occur early in the pathogenesis of AD and in AβPP tg mice and to correlate with the cognitive impairment and deficits in long-term potentiation. Previous work in the AβPP tg has reported the emergence of behavioral deficits at 3–6 months of age [29]. It is interesting to note that this correlates with the emergence of the pE(3)Aβ deposits, however more detailed studies are needed in order to establish a causative relationship.…”

A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression

“…Moreover, hippocampal projection fibers of BFCNs are modulated by p75 NTR in WT mice [28] as are ChAT-containing neurites in APP L/S mice [8]. Finally, mild cognitive deficits are first seen in APP L/S mice at 3 months [21], are significantly worse at 6–8 months, and then progressively increase [14], [16], [20], [21].…”