Neurotoxicity on hippocampal neurons is mediated by specific activation patterns of microglia

Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases

“…Aging affects cells, organs, and functions in various ways, particularly in the CNS ( Ramirez et al, 2008 ; von Bernhardi et al, 2019 ). Aging is characterized by a low-grade inflammatory condition and the progressive deterioration of various physiological functions of the organism, being recognized as the most robust risk factor for neurodegenerative diseases like Alzheimer’s disease (AD) ( Guerreiro and Bras, 2015 ).…”

“…For instance, in a patient diagnosed with AD at age 75, pathophysiological changes started when the person was 50–55 years old. Aged individuals have also changes on the immune system, known as immune senescence ( Jones et al, 2010 ), characterized by decreased adaptive immunity, making the subject more susceptible to infections and tumors, and exacerbated innate immune function ( von Bernhardi et al, 2019 ) favoring chronic neuroinflammation, which appears to be also associated with the appearance of neurodegenerative pathologies ( Block et al, 2007 ; von Bernhardi, 2007 ; Gao and Hong, 2008 ).…”

“…On the other hand, neuroinflammation promotes neurotoxicity by inducing cytotoxic activation of microglia ( Ramirez et al, 2008 ), inhibition of Aβ clearance ( von Bernhardi, 2007 ), and synergistic deleterious effects promoting neuronal death ( Nguyen et al, 2002 ; von Bernhardi and Eugenin, 2012 ). Thus, as a global effect of aging, microglia switch from a neuroprotective to a more cytotoxic phenotype ( Banati et al, 1993 ; von Bernhardi et al, 2010 , 2015 , 2019 ; Streit et al, 2021 ). Accordingly, microglia from older individuals present morphological evidence of activation compared with young ones ( Streit et al, 2004 ; von Bernhardi, 2007 ; von Bernhardi et al, 2010 , 2011 ), elevated basal levels of inflammatory cytokines, such as IL6 and IL1β ( Ye and Johnson, 1999 ; Sierra et al, 2007 ), decreased signaling by suppressor of mothers against decapentaplegic 3 (Smad3)-TGFβ in inflammation ( Tichauer and von Bernhardi, 2012 ), decreased Aβ-induced phagocytosis ( Floden and Combs, 2011 ), and increased ROS production ( Tichauer and von Bernhardi, 2012 ) and oxidative stress ( von Bernhardi and Eugenin, 2012 ; Tichauer et al, 2014 ).…”