Intracerebroventricular Injection of Amyloid-&amp;#946; Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits

Kim, Hye Yun; Lee, Dongkeun K.; Chung, Bo Ryehn; Kim, Hyunjin V.; Kim, Youngsoo

doi:10.3791/53308

Cited by 105 publications

(92 citation statements)

References 16 publications

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“…The observed significant long-term spatial memory impairment is in line with studies conducted in the past examining the acute effect of Aβ injection on cognitive memory and function (Kim et al, 2016;Kasza et al, 2017). Mice treated with acute intracerebroventricular Aβ displayed statistically significant spatial memory impairment in Y maze test 3 days post-injection (Kim et al, 2016). Rats displayed impaired spatial memory on Morris water maze test and impaired synaptic plasticity 7 days post-intracerebroventricular Aβ 1−42 injection (Kasza et al, 2017) but this timepoint might reflect more long-term consequences of the neurotoxic insult.…”

Section: Vglut Expression Alterations 3 Days Post-aβ Injectionsupporting

confidence: 90%

Section: Vglut Expression Alterations 3 Days Post-aβ Injectionsupporting

confidence: 88%

“…Acute exposure of rats to Aβ oligomers for 1, 3, 7, 21 days has shown pathophysiological alterations, including delayed increase in activated microglia and a decreased cholinergic neuronal number observed at day 21 (Wong et al, 2016). There are a limited number of studies that have examined acute Aβ 1−42 -induced behavioral deficits (Kim et al, 2016;Kasza et al, 2017). Therefore, we have performed a thorough behavioral examination 3 days post-Aβ 1−42 injection.…”

Section: Introductionmentioning

confidence: 99%

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The Acute Effects of Amyloid-Beta1–42 on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus

et al. 2020

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Alzheimer's disease (AD) is the leading type of dementia worldwide. Despite an increasing burden of disease due to a rapidly aging population, there is still a lack of complete understanding of the precise pathological mechanisms which drive its progression. Glutamate is the main excitatory neurotransmitter in the brain and plays an essential role in the normal function and excitability of neuronal networks. While previous studies have shown alterations in the function of the glutamatergic system in AD, the underlying etiology of beta amyloid (Aβ 1−42) induced changes has not been explored. Here we have investigated the acute effects of stereotaxic hippocampal Aβ 1−42 injection on specific glutamatergic receptors and transporters in the mouse hippocampus, using immunohistochemistry and confocal microscopy 3 days after Aβ 1−42 injection in aged male C57BL/6 mice, before the onset of neuronal cell death. We show that acute injection of Aβ 1−42 is sufficient to induce cognitive deficits 3 days post-injection. We also report no significant changes in glutamate receptor subunits GluA1, GluA2, VGluT1, and VGluT2 in response to acute injection of Aβ 1−42 when compared with the ACSF-vehicle injected mice. However, we observed increased expression in the DG hilus and ventral stratum (str.) granulosum, CA3 str. radiatum and str. oriens, and CA1 str. radiatum of the GluN1 subunit, and increased expression within the CA3 str. radiatum and decreased expression within the DG str. granulosum of the GluN2A subunit in Aβ 1−42 injected mice compared to NC, and a similar trend observed when compared to ACSF-injected mice. We also observed alterations in expression patterns of glutamatergic receptor subunits and transporters within specific layers of hippocampal subregions in response to a microinjection stimulus. These findings indicate that the pathological alterations in the glutamatergic system observed in AD are likely to be partially a result of both acute and chronic exposure to Aβ 1−42 and implies a much more complex circuit mechanism associated with glutamatergic dysfunction than simply glutamate-mediated excitotoxic neuronal death.

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Section: Vglut Expression Alterations 3 Days Post-aβ Injectionsupporting

confidence: 90%

Section: Vglut Expression Alterations 3 Days Post-aβ Injectionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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The Acute Effects of Amyloid-Beta1–42 on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus

et al. 2020

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“…Prior to drug injections, mice were anesthetized with 2% isoflurane and placed in a stereotaxic head frame on a heating pad. For each mouse, the bregma was located without exposure of the skull (54). A guarded 23-gauge needle was used to punch a hole 0.2 mm posterior to the bregma and 1.0 mm lateral to the midline.…”

Section: Intracerebroventricular (Icv) Injectionmentioning

confidence: 99%

Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation

et al. 2019

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authors contributed equally to this work.One-sentence summaries: A human Neuropeptide S Receptor 1 (NPSR1) mutation found in natural short sleepers renders mutant mice to be short sleepers with more resilience to memory deficits caused by sleep deprivation.Abstract: Sleep is a crucial physiological process for our survival and cognitive performance, yet the factors controlling human sleep regulation remain poorly understood. Here we identified a missense mutation in a G-protein coupled Neuropeptide S Receptor 1 (NPSR1) that is associated with a natural short sleep phenotype in humans. Mice carrying the homologous mutation exhibit less sleep time despite increased sleep pressure. They are also resistant to contextual memory deficits associated with sleep deprivation. In vivo, the mutant receptors are more sensitive to Neuropeptide S ligand treatment. These results highlight an important role for the NPS/NPSR1 pathway in human sleep duration regulation and in the connection between sleep homeostasis and memory consolidation.

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“…To induce Aβ aggregates by injecting Aβ species in vivo, an AD mouse model is typically a prerequisite [19]. Kim et al injected Aβ peptides in normal mice, inducing AD-like cognitive deficits [36]. However, they did not demonstrate the formation of plaques in the injected area.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Boza-Serrano¹,

Ruiz

Sánchez-Varo³

et al. 2018

Preprint

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Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice, and found specifically expressed in microglia associated with Aβ plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to Aβ plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure Aβ. Importantly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of insoluble Aβ aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and Aβ aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD. #Corresponding Authors:Tomas Deierborg (tomas.deierborg@med.lu.se), Jose Luis Venero (jlvenero@us.es) and Antonio Boza-Serrano (antonio.boza_serrano@med.lu.se). Keywords:Alzheimer's disease, Galectin-3, TREM2, Microglial, Amyloid Aggregation. classical hallmarks of AD include the formation of amyloid-beta (Aβ) plaque deposits and of neurofibrillary tangles (NFT) containing abnormal hyperphosphorylation of tau. Over the course of the disease, the deposition of Aβ and the formation of the NFTs appear to be correlated with the on-going hippocampal neurodegeneration [7]. Hippocampal neurodegeneration has a negative effect on the cognitive ability of patients, especially short-term memory, which is impaired. The mechanisms triggering the deposition of the Aβ or the formation of NFT are currently unclear. However, several mechanisms and factors have been suggested to be involved in ...

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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits

Cited by 105 publications

References 16 publications

The Acute Effects of Amyloid-Beta1–42 on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus

The Acute Effects of Amyloid-Beta1–42 on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus

Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

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