Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Abstract

Alzheimer's disease is a neurodegenerative disease affecting the aging population. A key neuropathological feature of the disease is the over-production of amyloid-beta and the deposition of amyloid-beta plaques in brain regions of the afflicted individuals. Throughout the years scientists have generated numerous Alzheimer's disease mouse models that attempt to replicate the amyloid-beta pathology. Unfortunately, the mouse models only selectively mimic the disease features. Neuronal death, a prominent effect in the brains of Alzheimer's disease patients, is noticeably lacking in these mice. Hence, we and others have employed a method of directly infusing soluble oligomeric species of amyloid-beta -forms of amyloid-beta that have been proven to be most toxic to neurons -stereotaxically into the brain. In this report we utilize male C57BL/6J mice to document this surgical technique of increasing amyloid-beta levels in a select brain region. The infusion target is the dentate gyrus of the hippocampus because this brain structure, along with the basal forebrain that is connected by the cholinergic circuit, represents one of the areas of degeneration in the disease. The results of elevating amyloid-beta in the dentate gyrus via stereotaxic infusion reveal increases in neuron loss in the dentate gyrus within 1 week, while there is a concomitant increase in cell death and cholinergic neuron loss in the vertical limb of the diagonal band of Broca of the basal forebrain. These effects are observed up to 2 weeks. Our data suggests that the current amyloid-beta infusion model provides an alternative mouse model to address region specific neuron death in a short-term basis. The advantage of this model is that amyloid-beta can be elevated in a spatial and temporal manner. Video LinkThe video component of this article can be found at

Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide

“…More interestingly, Spns2 deficiency in mice showed improved working memory in a Y-Maze test and reduced neuronal cell death after Aβ42 treatment in vivo ( Figure 7). This is consistent with previous reports that Aβ42 oligomer infusion induces neurodegeneration (Jean et al, 2015;Takuma, Tomiyama, Kuida, & Mori, 2004;Wan et al, 2010).…”

“…Neuroinflammation contributes to impaired cognitive function (Lee et al, 2008;Qin et al, 2007;Shamim & Laskowski, 2017). To investigate the role of Spns2 in microglia activation in vivo, we stereotaxically injected Aβ42 oligomers into the subgranular zone of Spns2KO mouse brains (AP: −2 mm; ML: AE1.3 mm; DL: −2 mm) (Jean, Baleriola, Fa, Hengst, & Troy, 2015). Aβ42 oligomer has been found to induce microglia activation in vitro and in vivo (Jean et al, 2015;Sasaki, Yamaguchi, Ogawa, Sugihara, & Nakazato, 1997;Wu, Combs, Cannady, Geldmacher, & Herrup, 2000).…”

“…To investigate the role of Spns2 in microglia activation in vivo, we stereotaxically injected Aβ42 oligomers into the subgranular zone of Spns2KO mouse brains (AP: −2 mm; ML: AE1.3 mm; DL: −2 mm) (Jean, Baleriola, Fa, Hengst, & Troy, 2015). Aβ42 oligomer has been found to induce microglia activation in vitro and in vivo (Jean et al, 2015;Sasaki, Yamaguchi, Ogawa, Sugihara, & Nakazato, 1997;Wu, Combs, Cannady, Geldmacher, & Herrup, 2000). After 6 weeks, we carried out a Y-maze behavioral test to assess spatial working memory affected by Spns2KO.…”

Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor

“…First singular or just a few cells being affected, over time a burden of cell deaths accumulates that finally ends in Alzheimer's Dementia whenever critical brain regions and their redundant structures are affected (Jean et al, 2015 ). In line, to block free amyloid by specific antibodies allows slowing down Alzheimer's Dementia as recently indicated by the nowadays moon lading of Siemers and colleges.…”

Optimized‐SopungSunkiwon, a Herbal Formula, Attenuates Aβ Oligomer‐Induced Neurotoxicity in Alzheimer’s Disease Models

“…Animal treatment and maintenance were carried out in accordance with the Principle of Laboratory Animal Care (NIH publication number 85-23, revised 1985) and the Animal Care and Use Guidelines of Kyung Hee University, Seoul, Korea. Stereotaxic injections of A β O 1–42 into mouse hippocampi were performed as previously described [ 18 , 22 ]. In brief, mice were anesthetized and mounted in a stereotaxic apparatus (myNeuroLab, St. Louis, MO, USA).…”