Additive Microglia-Mediated Neuronal Injury Caused by Amyloid-β and Bacterial TLR Agonists in Murine Neuron-Microglia Co-Cultures Quantified by an Automated Image Analysis using Cognition Network Technology

Abstract

Activated microglia is considered to be involved in the progression of Alzheimer's disease (AD). We investigated the effect of amyloid-β(1-40) (Aβ(40) and exogenous agonists of Toll-like receptor (TLR) 1/2 (Pam(3)CSK(4)) and TLR4 (LPS) on neurons in primary murine neuron-microglia co-cultures. Neuronal viability, assessed by quantifying the number of intact neuronal extensions and their crossings using a newly developed Definiens Cognition Network Technology-based method, was significantly decreased after treatment with Pam(3)CSK(4), LPS, and Aβ(40). Combined treatment with Aβ(40) and Pam(3)CSK(4) or LPS had an additive effect. Hence, in patients with AD, synergistic microglial activation by Aβ and bacterial products during infections might contribute to disease progression.

Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 by macrophages and increases the resistance of mice against infections

“…It probably also is the pathophysiological basis of the deterioration of patients with neurodegenerative diseases during infections. The functional outcome of TLR-induced activation of microglia in the CNS depends on a subtle balance between protective and harmful effects [48-50]. For this reason, activation of the TLR or NOD system aiming at increasing the resistance to infections bears the risk of inducing collateral damage to the vessels, the nervous system or other organs.…”

Fungal encephalitis in human autopsy cases is associated with extensive neuronal damage but only minimal repair

“…Neuronal injury and repair in human fungal encephalitis 621 NAN 2014; 40: 610-627 sis and intracellular killing of pathogens, on the other hand activated microglia can destroy axons, dendrites and neuronal somata [39][40][41][42][43]. On average, microglial activation and astrocyte proliferation was stronger in fungal encephalitis than in septic-metastatic encephalitis and bacterial meningitis suggesting that the inflammatory involvement of brain tissue was more severe in fungal encephalitis than in septic-metastatic encephalitis and bacterial meningitis [17,37].…”

Toll-like receptor stimulation increases phagocytosis of Cryptococcus neoformans by microglial cells

“…Extracellular amphotericin B was necessary for the whole incubation time to avoid migration of viable cryptococci from the interior of the microglial cells to the medium, and subsequent extracellular growth. Microglia activated by TLR agonists produce proinflammatory cytokines (for example, TNF-α, IL-1 and IL-6) and nitric oxide, which can cause neuronal injury [32-36]. For this reason, the approach described here will have to be tested in vivo for efficacy and with respect to the possible induction of unintended neuronal injury.…”