Higher CSF sTREM2 and microglia activation are associated with slower rates of beta‐amyloid accumulation

Abstract

Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid‐beta (Aβ) accumulation remains unclear. To address this question, we pursued a two‐pronged translational approach. Firstly, in non‐demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross‐sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the AppNL‐G-F mouse model of amyloidosis, we studied baseline 18F‐GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co‐pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5‐to‐10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation.

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

“…This formulation played a major role in prompting us to use dual RNA in situ hybridization and immunohistochemistry in the current study in which we sought to determine With the inclusion of Tyrobp as a PIG gene 43 and because of our prior validation of its actions as a driver of AD 9,23,27,28 , we hypothesized that constitutive overexpression of microglial Tyrobp via transgenesis would alter both amyloid and tau pathologies. In APP/PSEN1 mice, Tyrobp upregulation decreased the amyloid burden, similar to what occurs with the upregulation of Trem2 26 and supported by a recent report showing that higher microglia activation shows protective effects on subsequent amyloid accumulation 45 . In MAPT P301S mice, we previously reported that deficiency of Tyrobp increased TAU phosphorylation and spread 23 , and were puzzled, therefore, to observe a similar increase in TAU phosphorylation in the MAPT P301S mice with overexpression of Tyrobp.…”

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation

“…However, these authors did show that WT sTREM2 bound strongly to amyloid plaques ( 34 ), consistent with our results. Our studies provide a potential explanation of the clinical observation of slower rates of cognitive and clinical decline in patients with MCI or AD who have higher levels of sTREM2 in the CSF ( 20 , 21 ) and slower rates of amyloid deposition in healthy controls and MCI patients with higher sTREM2 levels in CSF ( 22 ). They also provide a potential explanation for the beneficial effects of infusing or expressing sTREM2 into the brain of mouse models of AD ( 16 ).…”

“…Fifth, mild cognitive impairment (MCI) and AD patients with higher sTREM2 levels in CSF have slower brain atrophy, cognitive decline, and clinical decline ( 20 , 21 ), consistent with sTREM2 inhibiting AD progression. Sixth, healthy controls and MCI patients with higher sTREM2 levels in CSF have slower progression of amyloid and tau deposition ( 22 ), consistent with sTREM2 inhibiting Aβ aggregation and subsequent tau pathology.…”

The role of innate immune genes in Alzheimer's disease

“…Soluble (s)TREM2 is elevated in Alzheimer's disease cerebrospinal fluid (CSF) compared with controls [ 83 ]. Increased sTREM2 in CSF is associated with reduced cognitive decline in Alzheimer's disease [ 84 ] and with slower rates of Aβ accumulation [ 85 ]. sTREM2 also protects against amyloid disease by enhancing microglial activity in 5xFAD mice [ 86 ].…”