Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Kemppainen, Susanna; Rantamäki, Tomi; Jerónimo-Santos, André; Lavasseur, Gregoire; Autio, Henri; Karpova, Nina N.; Kärkkäinen, Elisa; Stavén, Saara; Miranda, Hugo Vicente; Outeiro, Tiago F.; Diógenes, Maria José; Laroche, Serge; Davis, Sabrina; Sebastião, Ana M.; Ċastrén, Eero; Tanila, Heikki

doi:10.1016/j.neurobiolaging.2011.11.006

Cited by 79 publications

(68 citation statements)

References 54 publications

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“…Instead, the pathology is characterized by gradual increase in the number of amyloid plaques surrounded by chronic neuroinflammation [30] and abnormalities in synaptic microstructure [29]. We found no effect of CDNF treatment on amyloid pathology, which is in line with our earlier observations of no change in brain amyloid load after manipulation of functional TrkB-receptor levels [27] or partial BDNF gene knockout [28], as well as with a recent study reporting lack of effect on amyloid levels by GDNF gene therapy in APP/PS1/tau transgenic mice [9]. Neither could we verify any obvious anti-inflammatory effect of CDNF around the injection site.…”

Section: Discussionsupporting

confidence: 91%

“…In addition, CDNF effect on memory is behaviorally distinct from that of widely studied BDNF. In our previous studies in female APP/PS1 and WT mice, transgenic overexpression of the dominant negative TrkB.T1 receptor impaired, while overexpression of functional TrkB.TK receptor improved acquisition of the Morris swim task without having a significant effect on memory retention in the probe trial [27]. Similarly, partial knockout of BDNF impaired Morris swim task acquisition but did not influence performance on the probe trial [28].…”

Section: Discussionmentioning

confidence: 84%

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Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

Kemppainen

Lindholm

Galli

et al. 2015

Behavioural Brain Research

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 84%

Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

Kemppainen

Lindholm

Galli

et al. 2015

Behavioural Brain Research

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“…These mice were engineered to express murine amyloid precursor protein (APP) with the human β-amyloid (Aβ) amino acid sequence harboring mutations that cause a familial form of AD [the Swedish mutation APP(K595N/M596L): APPswe] together with a mutated form of presenilin 1 (PS1 with exon 9 deleted: PS1dE9) (19). Although no model of AD fully recapitulates the human disease (20), APP.PS1 mice are well suited for our investigations because they exhibit (i) cholinergic defects (8-12), (ii) high production of Aβ peptides in brain and accumulation of amyloid plaques (21), and (iii) cognitive impairments (12,(22)(23)(24)(25)(26). We elected to study animals at 5 and 10 mo of age.…”

mentioning

confidence: 99%

BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer’s disease

Burke¹,

Norman²,

Haydar

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5-and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.acetylcholine | APPswe PS1dE9 mice | growth/differentiation factor 2 | juvenile protective factors B asal forebrain cholinergic neurons (BFCN) project to the hippocampus and cerebral cortex where the release of their neurotransmitter, acetylcholine (ACh), is central for the processes of learning, memory, and attention throughout life (1). The acquisition of the cholinergic phenotype by these neurons during development is induced by bone morphogenetic protein 9 (BMP9), also known as growth/differentiation factor 2 (GDF2), which is expressed in the fetal basal forebrain (2). Application of BMP9 to basal forebrain cell cultures and into the cerebral ventricles of developing mouse embryos (2) and adult mice (3) significantly increases ACh production. Moreover, the idea that the BMP9-signaling pathway may be a master regulator of the BFCN phenotype is supported by evidence showing that BMP9 is sufficient to induce BFCN-like features in human embryonic stem cell-derived neural progenitor cells (4) and that, in rodent basal forebrain cell cultures, BMP9 induces the BFCN transcriptome (5). Recent studies indicate that intracerebroventricularly (i.c.v.)-infused BMP9 fully prevents the cholinergic dedifferentiation (i.e., loss of cholinergic markers) of axotomized BFCN in mice (3). Taken together, these data provid...

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“…We have previously shown that developmental MeHg-exposure induced long-lasting depression-like behavior and decreased hippocampal expression of the critical for brain functioning gene brain-derived neurotrophic factor (Bdnf), in adult mice (Onishchenko et al, 2008). Impaired Bdnf expression or signaling through its receptor TrkB was linked to learning and memory problems and to development of anxiety in several transgenic and stress models of brain disorders (Minichiello et al, 1999; Soliman et al, 2010; Karpova et al, 2011; Kemppainen et al, 2012; Lai et al, 2012). Developmental MeHg-exposure, however, did not alter the full-length TrkB transcript levels at least in the hippocampus (Onishchenko et al, 2008), and no other study linking the long-term effect of perinatal MeHg treatment to TrkB expression has been performed.…”

Section: Introductionmentioning

confidence: 99%

TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury

Karpova

Lindholm

Kulesskaya

et al. 2014

Front. Behav. Neurosci.

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Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure.

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Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Cited by 79 publications

References 54 publications

Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer’s disease

TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury

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