Altered Innate Immune and Glial Cell Responses to Inflammatory Stimuli in Amyloid Precursor Protein Knockout Mice.

Anna Carrano,Pritam Das,Michelle L Block

doi:10.1371/journal.pone.0140210

Abstract

Amyloid precursor protein (APP) and its cleaved products have been reported to have important functions in CNS health, including in memory and synapse formation, cell survival and neuroprotection. Furthermore APP and its cleaved products have been shown to be transiently increased in response to various CNS stressors, suggesting a role in response to acute cellular injury. In an attempt to further understand the function of APP in response to CNS injury, we have used intracranial LPS injection as an inflammatory injury model in APP knock out mice (APPKO). Our data show that innate immune responses to LPS injection is significantly blunted in APPKO mice compared to APP sufficient wild type (BL6) mice. Morphologically, glial cells in APPKO mice appear less reactive, with shorter ramified processes and smaller cell bodies in response to LPS. Additionally, quantitative RT-PCR analysis for several glia markers and innate immune cytokine levels (e.g. TNFα, IL-6, IL-1β and IL-10) showed significantly reduced expression levels in LPS injected APPKO mice. In vitro cell culture assays confirmed this attenuated response to LPS stimulation by primary microglial cells isolated from APPKO mice. Our data suggests that APP full length protein and/or its cleaved products are necessary to mount a complete and effective innate immune cell response to inflammatory injury.

Highlights

Alzheimer disease (AD) is the most common cause of dementia for which an effective treatment is not available yet
APP knock out mice (APPKO) and wild type BL6 mice following hippocampal LPS injections were sacrificed at day 1 and 3 post surgery and analyzed for immuno-histochemical -staining of microglial marker Iba1. (Fig 1A–1H) shows that LPS stimulation induces microglia activation and proliferation at 3 days post injection in both 3 months old APPKO mice and wild type BL6 mice
Prior studies investigating the physiological functions of amyloid precursor protein (APP) and its cleavage fragments suggest that it plays critical roles in many CNS cellular functions, including synaptogenesis, synaptic plasticity, memory, neurogenesis, and neuroprotection [3]

Summary

Introduction

Alzheimer disease (AD) is the most common cause of dementia for which an effective treatment is not available yet. The most widely accepted hypothesis states that AD is initially triggered by the abnormal accumulation of amyloid β-peptide (Aβ) in the brain, which in turn initiates a pathogenic cascade that leads to neuronal death and dementia [1]. Aββ is cleaved from a long membrane-bound precursor, the amyloid precursor protein (APP), by two consecutive cleavages. Β- and γ-secretases are the enzymes that liberate the N and C termini of Aβ, respectively [2]. Much is known about Aβ pathophysiology, the normal physiological functions of APP and its cleaved fragments are not well understood, in response to brain aging and inflammation. Evidence to suggest that APP and its cleavage. PLOS ONE | DOI:10.1371/journal.pone.0140210 October 8, 2015

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