Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1

Abstract

Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-beta (Abeta) accumulation and related cognitive impairments. Although deficits in hippocampus-dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Abeta and temporal memory deficits. This behavioral test requires hippocampus-dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild-type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus-specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's beta-secretase (beta-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Abeta oligomers found in Tg6799+ mouse brains returned to wild-type control levels without changes in APP/PS1 transgene expression in BACE1-/- * Tg6799+ bigenic mouse brains, suggesting Abeta oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Abeta-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Abeta oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

“…Sections from age-matched dtg APP/PS1 mice and WT controls were histochemically stained by Congo Red to assess age-related changes in AD-type betaamyloid (Aβ) plaques. This study confirmed agerelated increases in Aβ plaques beginning at 5 months of age and increasing progressively by 12 and 15 months, in agreement with a previous study in a different cohort of the same line of dtgAPPswe/ PS1dE9 (Ohno et al 2006).…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…We used 5XFAD transgenic mice (Tg6799 line) that coexpress and co-inherit FAD mutant forms of human APP (the Swedish mutation: K670N, M671 L; the Florida mutation: I716V; the London mutation: V717I) and PS1 (M146 L; L286V) transgenes under transcriptional control of the neuron-specific mouse Thy-1 promoter Ohno et al, 2006). 5XFAD lines (B6/SJL genetic background) were maintained by crossing hemizygous transgenic mice with B6/SJL F1 breeders (Taconic, Hudson, NY).…”

“…We used 5XFAD transgenic mice that co-overexpress human APP and presenilin 1 (PS1) harboring five familial AD (FAD) mutations under control of the neuron-specific Thy-1 promoter Ohno et al, 2006). 5XFAD mice start to develop visible amyloid deposition as early as 2 months of age consistent with their dramatically accelerated Ab42 production because of a combination of the multiple FAD mutations, thus representing an early onset and aggressive amyloid mouse model .…”

“…5XFAD mice start to develop visible amyloid deposition as early as 2 months of age consistent with their dramatically accelerated Ab42 production because of a combination of the multiple FAD mutations, thus representing an early onset and aggressive amyloid mouse model . At 4-6 months of age, 5XFAD mice start to show impairments in hippocampus-dependent learning and memory as tested by the Y-maze, Morris water maze, and contextual or trace fear conditioning paradigms (Kimura and Ohno, 2009;Oakley et al, 2006;Ohno et al, 2006). These behavioral deficits are observed concomitant with the onset of hippocampal CA1 synaptic dysfunctions such as reduced basal transmission and long-term potentiation (LTP: a synaptic plasticity model for learning and memory) (Kimura and Ohno, 2009).…”

A Ganglioside-induced Toxic Soluble Aβ Assembly

“…Furthermore, the inhibition of long term potentiation and the impairment of cognitive function in vivo can be induced by natural A␤ oligomers (9,24) or a specific A␤ assembly called A␤ ૽ 56, which has recently been isolated from Tg2576 mice (expressing a human amyloid precursor protein variant-linked familial AD) (25). Additionally, recent studies using AD mouse models revealed that soluble A␤ assemblies may play a role in the induction of tau pathology (26) and that the genetic deletion of ␤-secretase, which is responsible for A␤ production, rescues temporal memory deficit in conjunction with the suppression of the increase in the levels of cerebral A␤-derived diffusible ligands (27). These lines of evidence indicate the pathological relevance of these soluble A␤ assemblies in AD development.…”