ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice

Liraz, Ori; Boehm-Cagan, Anat; Michaelson, Daniel M.

doi:10.1186/1750-1326-8-16

Cited by 97 publications

(113 citation statements)

References 103 publications

(124 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The study revealed that the performance of the apoE4 mice in the object recognition and Morris water maze was impaired relative to that of the apoE3 mice and that it was also impaired in the contextual but not in the cued fear conditioning response.These findings are in accordance with previous results obtained utilizing a dry version of the Morris water maze and fear conditioning test results, which were obtained using young apoE4 mice [23,30]. They also extend previous studies that revealed that adult apoE4 mice are cognitively impaired [32,34,36,37,41,42,43,44] and suggest that, like in humans, the apoE4-driven cognitive impairments begin early in life [45,46].…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Hippocampus-Related Cognitive Impairments in Young apoE4 Targeted Replacement Mice

Salomon-Zimri

Boehm-Cagan²,

Liraz³

et al. 2013

Neurodegener Dis

Self Cite

View full text Add to dashboard Cite

We presently investigated the effects of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, on the cognitive performance of young targeted replacement apoE4 mice. We revealed that these mice were impaired in the object recognition and Morris water maze tests, both of which are associated with hippocampal learning and memory, relative to that of the apoE3 mice. These results are consistent with previous histological and biochemical findings that hippocampal neurons are specifically affected by apoE4. The suggestion that the behavioral impairments of the apoE4 mice are related to the hippocampal neuropathology of these mice is further supported by the fear conditioning test. This test revealed that the performance of the apoE4 mice in the contextual component, which is hippocampus related, was impaired, whereas their cued test response, which is amygdala driven, was not. The stress levels of the apoE4 and apoE3 mice, as unraveled by the light/dark anxiety test, were similar, suggesting that the observed cognitive impairments of the apoE4 mice are not related to differences in the basal anxiety levels of these mice. In conclusion, the present study shows that young apoE4 targeted replacement mice are impaired in numerous hippocampus-related learning and memory tasks.

show abstract

Section: Discussionsupporting

confidence: 93%

“…These biochemical findings were in accordance with impaired performance of the apoE4 mice in a dry version of the Morris water maze [23]. …”

Section: Introductionsupporting

confidence: 66%

Hippocampus-Related Cognitive Impairments in Young apoE4 Targeted Replacement Mice

Salomon-Zimri

Boehm-Cagan²,

Liraz³

et al. 2013

Neurodegener Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cdk5 may be influenced by or interact with both pathways, and its activation triggers DNA damage, cell cycle activation and neurodegeneration [231] . Non-Aβ factors such as Tau and ApoE also contribute to AD pathology [232] . All these pathways can lead to synaptic dysfunction, neurodegeneration and AD.…”

Section: Non-aβ Hypothesismentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

View full text Add to dashboard Cite

Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

show abstract

“…Note that the present line of apoE4-TR mice was crossed with C57Bl mice from Harlan, which lack the pre-synaptic protein synuclein (Specht and Schoepfer 2001). Preliminary findings utilizing apoE4 mice crossed with C57Bl mice, which have normal synuclein levels, suggest that phenotypes not directly related to the nerve terminal (e.g., apoE4-driven accumulation of Ab and hyperphosphorylated tau; Liraz et al 2013) are not affected by synuclein deficiency. The extent to which the apoE4-driven cholinergic impairments are accentuated by the lack of synuclein remains to be determined.…”

Section: Discussionmentioning

confidence: 98%

“…However, since apoE4 also affects non-cholinergic synaptic parameters, e.g. reduction of the pre-synaptic glutamatergic transporter VgluT in hippocampus (Liraz et al 2013) or increase in VgluT transporter and disturbance of the glutamate-glutamine cycle in whole brain (Dumanis et al 2013), additional brain structure-specific mechanisms may play a role in mediating the synaptic pathological effects of apoE4.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

Dolejší

Liraz

Rudajev

et al. 2015

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Keywords: acetylcholine release, Alzheimer's disease (AD), apolipoprotein E4 (apoE4), hippocampus. J. Neurochem. (2016) 136, 503-509. Cholinergic impairments are a hallmark of Alzheimer's disease (AD) (Craig et al. 2011). Genetic studies revealed that the allele e4 of apolipoprotein (APOE4 gene, apoE4 protein) is the most prevalent genetic risk factor for AD (Corder et al. 1993;Saunders et al. 1993). ApoE4 in AD and normal subjects is associated with biochemical cholinergic impairments (Reinvang et al. 2013). Furthermore, the response of apoE4-carrying AD patients (Braga et al. 2015) and normal controls (Pomara et al. 2004) to pharmacological cholinergic activation is impaired relative to corresponding subjects who express apolipoprotein E3 (apoE3), the AD benign isoform of this molecule. However, the extent to which apoE4 affects the release of acetylcholine (ACh) has not yet been determined.Transgenic mice have been prepared that express apoE4 or apoE3 under the regulation of either astrocytic or neuronal promoters, in addition to apoE-targeted replacement (TR) mice in which the endogenous mouse apoE was replaced by human apoE4 and apoE3 (Sullivan et al. 2011). Of these mice, the TR apoE mice have become the standard model in the field. Measurement of long-term potentiation (LTP) revealed a lower response in apoE4 TR mice ...

show abstract

ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice

Cited by 97 publications

References 103 publications

Hippocampus-Related Cognitive Impairments in Young apoE4 Targeted Replacement Mice

Hippocampus-Related Cognitive Impairments in Young apoE4 Targeted Replacement Mice

Amyloid beta: structure, biology and structure-based therapeutic development

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

Contact Info

Product

Resources

About