Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease.

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.

In atherosclerosis and Alzheimer’s disease, deposition of the altered-self components oxidized low-density lipoprotein (LDL) and β-amyloid triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and β-amyloid trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this novel heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and β-amyloid stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by co-receptor signaling events.

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of ␤-amyloid (A␤) before formation of senile plaques. However, persistent A␤ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear A␤ may decrease with age and progression of AD pathology. To determine the effects of aging and A␤ deposition on microglial ability to clear A␤, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the A␤-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the A␤-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1␤ (interleukin-1␤) and tumor necrosis factor ␣ (TNF␣), suggesting that there is an inverse correlation between cytokine production and A␤ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNF␣ decreased the expression of SRA and CD36 and reduced A␤ uptake. Our data indicate that, although early microglial recruitment promotes A␤ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to A␤ deposition downregulate genes involved in A␤ clearance and promote A␤ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.