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. 2017 Feb 24;3(2):e1601068.
doi: 10.1126/sciadv.1601068. eCollection 2017 Feb.

Differential Contribution of APP Metabolites to Early Cognitive Deficits in a TgCRND8 Mouse Model of Alzheimer's Disease

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Free PMC article

Differential Contribution of APP Metabolites to Early Cognitive Deficits in a TgCRND8 Mouse Model of Alzheimer's Disease

Valentine Hamm et al. Sci Adv. .
Free PMC article

Abstract

Alzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Aβ levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and γ oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Aβ-independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD.

Keywords: CA1 area; Hippocampus; Parvalbumin; amyloid beta; beta-CTF; gamma rhythm; recognition memory.

Figures

Fig. 1
Fig. 1. Semiquantitative analyses of the expression of APP and APP metabolites in 1- and 2-month-old TgCRND8 and control littermate mice.
(A) Western blot using the APP C-term antibody and quantification of APP and CTF levels. Note the specific increase in CTF levels in 2-month-old TgCRND8 mice compared to 1-month-old animals. (B) Hippocampal Aβ42 dosage in 1- and 2-month-old NTg and TgCRND8 mice. Aβ42 is below detection level in NTg animals. Despite a tendency to an age-dependent increase, Aβ levels remain low in both groups. *, difference between groups (**P < 0.01 and ***P < 0.0001); ND, non detectable.
Fig. 2
Fig. 2. Alterations in hippocampal oscillatory activity in pre-plaque TgCRND8 mice.
(A) Both TgCRND8 and NTg mice exhibit clear θ oscillations after sensory stimulation in all CA1 subfields. (B) No differences were found between genotypes in both total and θ power. γ Oscillatory activity was largely impaired in pre-plaque TgCRND8 mice in both the SG and FG range. (*, difference between groups; *P < 0.05 and **P < 0.01).
Fig. 3
Fig. 3. Alterations in hippocampal PV inhibitory network in pre-plaque TgCRND8 mice.
(A) Photomicrograph of the dorsal hippocampus from NTg and pre-plaque TgCRND8 mice [PV, red; SOM, green; 4′,6-diamidino-2-phenylindole (DAPI), blue]. Scale bars, 200 μm. No change was seen in the number of SOM interneurons whatever the hippocampal subfield. However, pre-plaque TgCRND8 mice exhibited a significant decrease in PV interneurons only in the CA1 area of the dorsal hippocampus. (B) Western blot analyses of hippocampal expression of NaV1.1 and NaV1.6 subunits. TgCRND8 mice exhibited a significant decrease in the expression of NaV1.6 and a clear tendency toward a decrease for the NaV1.1 subunit. *, difference between genotypes, Bonferroni post-hoc test, *P < 0.05 and **P < 0.01.
Fig. 4
Fig. 4. Behavioral characterization of 2-month-old pre-plaque TgCRND8 mice.
Pre-plaque TgCRND8 mice presented drastic alterations in the spatial object location task (A) and the object-place association task (B). However, they performed as controls in the Barnes maze task during the training phase and the probe test (C) as well as the novel object recognition task (D). *, difference between genotypes; #, different from chance.
Fig. 5
Fig. 5. Differential effect of β-secretase (LY2811376) and γ-secretase (semagacestat) inhibition on memory performances in pre-plaque TgCRND8 mice.
(A) Both β- and γ-secretase inhibitors rescued retention performances in the spatial object location task. (B) However, in the object-place association task, only the β-secretase inhibitor was effective. (C) LY2811376 and semagacestat differentially affected APP metabolite production. Although both treatments decreased Aβ levels, LY2811376 and semagacestat have opposite effects on β-CTF levels. (*, difference between genotypes * P < 0.05, ** P < 0.01, and *** P < 0.001); #, difference from chance; &, difference from TgCRND8 + vehicle (&&P < 0.01, &&&p < 0.001, and &&&&P < 0.0001).
Fig. 6
Fig. 6. Differential effect of β-secretase (LY2811376) and γ-secretase (semagacestat) inhibition on PV network.
β- and γ-secretase inhibitors did not rescue PV number in the CA1 area of the dorsal hippocampus. However, they both rescued NaV levels albeit using different mechanisms. Whereas semagacestat rescue both NaV1.1 and NaV1.6 levels, LY2811376 only rescued NaV1.6 levels. *, difference between groups (* P < 0.05, ** P < 0.01).
Fig. 7
Fig. 7. Differential effect of β-secretase (LY2811376) and γ-secretase (semagacestat) inhibition on dorsal hippocampal activation during the object-place association task.
(A) Photomicrograph of the dorsal hippocampus from NTg and pre-plaque TgCRND8 mice (c-Fos, green; DAPI, blue). Scale bars, 200 μm. Note the high number in c-Fos–labeled neurons in the dentate gyrus of NTg animals following the object-place association task. This dentate activation is absent in pre-plaque TgCRND8 mice. (B) LY2811376, but not semagacestat treatment, increased the number of activated cells in the dentate network during the task, albeit not to the level of NTg animals. *, difference between groups (**P < 0.01, ***P < 0.001).

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