Microglial Hyperreactivity Evolved to Immunosuppression in the Hippocampus of a Mouse Model of Accelerated Aging and Alzheimer’s Disease Traits

Abstract

Neuroinflammation is a risk factor for Alzheimer’s disease (AD). We sought to study the glial derangement in AD using diverse experimental models and human brain tissue. Besides classical pro-inflammatory cytokines, we analyzed chitinase 3 like 1 (CHI3L1 or YKL40) and triggering receptor expressed on myeloid cells 2 (TREM2) that are increasingly being associated with astrogliosis and microgliosis in AD, respectively. The SAMP8 mouse model of accelerated aging and AD traits showed elevated pro-inflammatory cytokines and activated microglia phenotype. Furthermore, 6-month-old SAMP8 showed an exacerbated inflammatory response to peripheral lipopolysaccharide in the hippocampus and null responsiveness at the advanced age (for this strain) of 12 months. Gene expression of TREM2 was increased in the hippocampus of transgenic 5XFAD mice and in the cingulate cortex of autosomal dominant AD patients, and to a lesser extent in aged SAMP8 mice and sporadic early-onset AD patients. However, gene expression of CHI3L1 was increased in mice but not in human AD brain samples. The results support the relevance of microglia activation in the pathways leading to neurodegeneration and suggest diverse neuroinflammatory responses according to the AD process. Therefore, the SAMP8 mouse model with marked alterations in the dynamics of microglia activation and senescence may provide a complementary approach to transgenic mouse models for the study of the neuroinflammatory mechanisms underlying AD risk and progression.

YKL-40 changes are not detected in post-mortem brain of patients with Alzheimer’s disease and frontotemporal lobar degeneration

“…Furthermore, we employed additional quantitative technologies, including the same immunoassay that is widely used for CSF analysis, which showed again no differences on YKL-40 levels between AD or FTLD and controls post-mortem brain. It is worth noting that a recent study showed no difference in CHI3L1 mRNA post-mortem tissue from early-onset AD cases, which was attributed to the younger age of these patients [ 54 ]. In line with our findings, a recent mass-spectrometry-based study detected YKL-40 changes in the CSF of AD patients but not in post-mortem tissue [ 55 ].…”

Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer′s Disease Neurodegeneration

“…Therefore, polarization of microglia to a reactive phenotype is an early event after Aβ 42 accumulation in these mice. TREM2 has also been found increased in the cerebral cortex of autosomal dominant AD patients [ 55 ]. Microglia play an important role in the innate immune response of the brain and their phenotypic changes may protect against neurodegeneration or worsen it when chronically activated [ 55 , 56 ].…”

“…TREM2 has also been found increased in the cerebral cortex of autosomal dominant AD patients [ 55 ]. Microglia play an important role in the innate immune response of the brain and their phenotypic changes may protect against neurodegeneration or worsen it when chronically activated [ 55 , 56 ]. Interestingly, maternal TPPU maintained low levels of Trem2 in both 5XFAD and WT mice.…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…However, microglia may get out of control and out of balance resulting in augmenting brain damage or sustaining chronic pathologies like neuroinflammation and inducing or enhancing neurodegeneration [ 28 , 35 ]. In such case, microglia may enhance brain aging [ 59 , 80 , 128 , 196 , 221 , 222 , 223 , 224 , 225 , 226 ].…”