SignificanceAlzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer’s disease (AD). Here we show that germline knockout of Trem2 or the TREM2 R47H variant reduce microgliosis around amyloid-β (Aβ) plaques and facilitate the seeding and spreading of neuritic plaque (NP) tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting development of peri-plaque tau pathologies.

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD).In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-␤ (A␤), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP swe /PS1 dE9 transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma A␤ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF A␤ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma A␤, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on A␤ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate A␤ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma A␤ in young and old mice, independent of neuronal insulin signaling.

Ising et al. report expression of anti-tau scFvs in the brain of a mouse model of tauopathy by AAV-mediated gene transfer. Treated mice show markedly decreased tau hyperphosphorylation and detergent-soluble tau species. Therefore, the Fc domain is not required to mediate effects in tauopathy.