SummaryTriggering receptor expressed on myeloid cells 2 (TREM2) is a microglia surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to dysfunctional response of microglia, which become apoptotic and fail to cluster around Aβ plaques. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining microglia response to Aβ accumulation.

Amyloid-β (Aβ) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease (AD). The factors regulating this process are only partly understood. Aβ aggregation is a concentration-dependent process that is likely to be dependent on changes in brain interstitial fluid (ISF) levels of Aβ. Using in vivo microdialysis, we found that ISF Aβ levels correlated with wakefulness. ISF Aβ levels also significantly increased during acute sleep deprivation and during orexin infusion, whereas they decreased with infusion of a dual orexin receptor antagonist. Importantly, chronic sleep restriction significantly increased and a dual orexin receptor antagonist decreased Aβ plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of AD.Alzheimer's disease (AD) is the most common cause of dementia. The accumulation of the amyloid-β (Aβ) peptide in the brain extracellular space is a critical event in the pathogenesis of AD. Aβ is produced by neurons and secreted into the brain interstitial fluid (ISF). An initiating factor in AD pathogenesis occurs when soluble, monomeric Aβ undergoes a conformational change and converts into forms such as oligomers, protofibrils, and fibrils. The accumulation of these forms of Aβ is concentration-dependent and confers toxicity (1). Elucidating factors that regulate soluble Aβ levels is important for understanding AD pathogenesis. Synaptic activity regulates the release of Aβ from neurons into the ISF (2,3). How ISF Aβ is regulated by normal physiology is poorly understood.To investigate ISF Aβ metabolism, we monitored hippocampal Aβ levels using in vivo microdialysis in both wild-type mice and human APP transgenic (Tg2576) mice, which express a mutated form of human amyloid precursor protein (APP) (4). ISF Aβ was assessed in Tg2576 mice at 3 months of age, several months earlier than Aβ deposition begins. We found diurnal variation of ISF Aβ levels. Aβ levels were significantly increased during the dark period compared to the light period (Fig. 1A). ISF Aβ levels fluctuated over a 24-hour period with mean levels during the light period being ~75% of mean Aβ levels during the dark period (Fig. 1B). ISF Aβ levels were significantly correlated with the amount of time spent awake (Fig. 1, C-D). Conversely, ISF Aβ levels were negatively correlated with the amount of time spent

Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.