The Interplay Between Beta-Amyloid 1-42 (Aβ1-42)-Induced Hippocampal Inflammatory Response, p-tau, Vascular Pathology, and Their Synergistic Contributions to Neuronal Death and Behavioral Deficits.

Beatriz Calvo-Flores Guzmán,Henry John Waldvogel,Michael Dragunow,Richard Lewis Maxwell Faull,Sarah Waters,Tessa Elizabeth Chaffey,Katie Peppercorn,Jordi Boix,Andrea Kwakowsky,Warren Perry Tate,Thulani Hansika Palpagama

doi:10.3389/fnmol.2020.552073

Beatriz Calvo-Flores Guzmán, Henry John Waldvogel + Show 9 more

Open Access

https://doi.org/10.3389/fnmol.2020.552073

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Abstract

Alzheimer’s disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ1–42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ1–42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ1–42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ1–42-injected mice compared with controls. These molecular changes in Aβ1–42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ1–42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a widespread loss of neuronal synapses and spines, the presence of intracellular neurofibrillary tangles (NFTs), and extracellular β-amyloid (Aβ) plaques (Huang and Mucke, 2012; Brun and Englun, 1981)
To assess cell layer-specific changes in tau pathology, density, and morphological changes in neuroinflammatory (GFAP, ionized calcium-binding adaptor molecule 1 (IBA-1), interferon-inducible protein 10 (IP-10), monocyte chemotactic protein-1 (MCP-1)) and vascular markers (ICAM-1, αSMA, CD31, fibrinogen) within the CA1 hippocampal region, free-floating fluorescent immunohistochemistry was performed on tissues from naïve control (NC), artificial cerebrospinal fluid (ACSF), scrAβ1–42- and Aβ1–42-injected mice
Aβ1–42-injected mice exhibited stronger immunostaining of glial fibrillary acidic protein (GFAP), Iba-1, CD31, and fibrinogen (Figure 1II), markers in the CA1 region at the injection site in comparison with controls

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a widespread loss of neuronal synapses and spines, the presence of intracellular neurofibrillary tangles (NFTs), and extracellular β-amyloid (Aβ) plaques (Huang and Mucke, 2012; Brun and Englun, 1981). Despite a large number of clinical trials, there is still currently no effective treatment to prevent, significantly delay, or ameliorate the debilitating symptoms of AD This is largely due to our limited understanding of the connecting factors underlying the disease, as well as the poor translation of promising treatment options derived from animal models to human clinical trials (Franco and Cedazo-Minguez, 2014; Souchet et al, 2018). With the prevalence of AD increasing alarmingly, it is crucial to develop animal models that more closely mimic the pathological and clinical symptoms of human AD Such a model has to be well characterized to document its limitations (Drummond and Wisniewski, 2017) and to determine whether it might effectively support drug screening for the development of novel and effective treatments for AD

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