Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer’s disease. Wild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed. High doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75 % lower-dose results in sustained elimination of ~30 % of microglia in both wild-type and 3xTg-AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg-AD mice treated for 6 or 12 weeks with lower levels of PLX5622 resulted in improved learning and memory. Aβ levels and plaque loads were not altered, but microglia in treated mice no longer associated with plaques, revealing a role for the CSF1R in the microglial reaction to plaques, as well as in mediating cognitive deficits. We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. Inhibition of the CSF1R at lower levels in 3xTg-AD mice prevents microglial association with plaques and improves cognition.

Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

SUMMARY: Tau, the microtubule‐associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. Under physiological conditions, tau regulates the assembly and maintenance of the structural stability of microtubules. In the diseased brain, however, tau becomes abnormally hyperphosphorylated, which ultimately causes the microtubules to disassemble, and the free tau molecules aggregate into paired helical filaments. A large body of evidence suggests that tau hyperphosphorylation results from perturbation of cellular signaling, mainly through imbalance in the activities of different protein kinases and phosphatases. In AD, it appears that ß‐amyloid peptide (Aß) plays a pivotal role in triggering this imbalance. In this review, we summarize our current understanding of the role of tau in AD and other tauopathies, and highlight key issues that need to be addressed to improve the success of developing novel therapies.

Increased brain deposition of amyloid β protein (Aβ) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-α (TNF-α)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of bothin vivoandin vitroapproaches. The intracerebroventricular injection of Aβ_1–40in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-α or iNOS reduced the cognitive deficit evoked by Aβ_1–40in mice. Similar results were obtained in TNF-α receptor 1 and iNOS knock-out mice. Aβ_1–40administration induced an increase in TNF-α expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Aβ_1–40led to activation of both JNK (c-Jun-NH₂-terminal kinase)/c-Jun and nuclear factor-κB, resulting in iNOS upregulation in both brain structures. The anti-TNF-α antibody reduced all of the molecular and biochemical alterations promoted by Aβ_1–40. These results provide new insights in mouse models of AD, revealing TNF-α and iNOS as central mediators of Aβ action. These pathways might be targeted for AD drug development.