Microglial Reactivity Correlates with Presynaptic Loss Independent of β‐Amyloid and Tau

Abstract

ObjectiveTriggering receptor expressed on myeloid cells‐2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable.MethodsWe identified 663 participants with baseline β‐amyloid (Aβ) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p‐Tau181), soluble TREM2 (sTREM2), PGRN, and growth‐associated protein‐43 (GAP‐43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aβ PET, CSF p‐Tau181, and CSF GAP‐43 cross‐sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation.ResultsHigher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p‐Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aβ burden was associated with attenuated CSF p‐Tau181 effects on CSF microglial biomarker increases. Independent of Aβ PET and CSF p‐Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP‐43 levels and faster rates of CSF GAP‐43 increase.InterpretationThese findings suggest that higher Aβ burden may attenuate the p‐Tau‐associated microglial responses, and TREM2‐related microglial reactivity may independently correlate with GAP‐43‐related presynaptic loss. This study highlights the two‐edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024

Association of soluble TREM2 with Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis

“…Additionally, the correlation between CSF sTREM2 levels and p-tau is a reliable indicator of cognitive decline in older individuals ( Ewers et al, 2019 ). Research indicates that microglial activation accelerates tau protein deposition ( Pascoal et al, 2021 ), and an increase of p-tau181 level is associated with a more rapid increase in CSF sTREM2 ( Lan et al, 2024 ). Moreover, CSF sTREM2 levels fluctuate as AD progresses; Aβ pathology leads to decreased sTREM2 levels, while increases in sTREM2 are associated with Tau deposition ( Ma et al, 2020 ).…”

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

“…However, in later stages of the disease, when tau accumulation is visible, astrogliosis also contributes to synaptic damage ( Woo et al, 2023 ). Moreover, elevated levels of sTREM2 in the CSF have been independently associated with presynaptic loss, as evidenced by increased Growth Associated Protein 43 (GAP-43) levels, suggesting that sTREM2-mediated microglial reactivity might drive synaptic dysfunction independently of β-amyloid and tau pathologies ( Lan et al, 2024 ). Additionally, concentrations of various forms of sTREM2, reported in the CSF of AD patients, have been found to inhibit LTP independently of amyloid plaque presence and related pathology.…”