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; Tessa Elizabeth Chaffey; Thulani Hansika Palpagama; Sarah Waters; Jordi Boix; Warren Perry Tate; Katie Peppercorn; Michael Dragunow; Henry John Waldvogel; Richard Lewis Maxwell Faull; Andrea Kwakowsky

doi:10.3389/fnmol.2020.552073

The Interplay Between Beta-Amyloid 1-42 (Aβ_1-42)-Induced Hippocampal Inflammatory Response, p-tau, Vascular Pathology, and Their Synergistic Contributions to Neuronal Death and Behavioral Deficits

Front Mol Neurosci. 2020 Nov 2:13:522073. doi: 10.3389/fnmol.2020.552073. eCollection 2020.

Affiliations

¹ Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
² Centre for Brain Research, NeuroDiscovery Behavioural Unit, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
³ Department of Biochemistry, University of Otago, Dunedin, New Zealand.
⁴ Centre for Brain Research, Department of Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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. Aβ_1-42 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 Aβ_1-42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ_1-42 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 Aβ_1-42-injected mice compared with controls. These molecular changes in Aβ_1-42-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 Aβ_1-42 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.

Keywords: Alzheiemer’s disease; cognition; neuroinflamamation; tau phosphorylation; β-amyloid.