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Alzheimer's disease (AD) is characterized by plaques containing amyloid-[beta] (Ap) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and A[beta], evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to A[beta] and its local toxicity. However, neocortical A[beta] pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human [TREM2.sup.CV] (common variant) or human [TREM2.sup.R47H]. [PS19-TREM2.sup.R47H] mice had significantly attenuated brain atrophy and synapse loss versus [PS19-TREM2.sup.CV] mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in [PS19-TREM2.sup.R47H] versus [PS19-TREM2.sup.CV] mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing [TREM2.sup.R47H] in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy., Introduction Alzheimer's disease (AD) is the leading cause of dementia worldwide and is the sixth leading cause of death in the United States (1). The histopathological hallmarks of AD are [...]

Introduction: Traumatic optic neuropathy (TON) is the optic nerve injury secondary to brain trauma leading to visual impairment and vision loss. Current clinical visual function assessments often fail to detect TON due to slow disease progression and clinically silent lesions resulting in potentially delayed or missed treatment in patients with traumatic brain injury (TBI)., Methods: Diffusion basis spectrum imaging (DBSI) is a novel imaging modality that can potentially fill this diagnostic gap. Twenty-two, 16-week-old, male mice were equally divided into a sham or TBI (induced by moderate Closed-Head Impact Model of Engineered Rotational Acceleration device) group. Briefly, mice were anesthetized with isoflurane (5% for 2.5 min followed by 2.5% maintenance during injury induction), had a helmet placed over the head, and were placed in a holder prior to a 2.1-joule impact. Serial visual acuity (VA) assessments, using the Virtual Optometry System, and DBSI scans were performed in both groups of mice. Immunohistochemistry (IHC) and histological analysis of optic nerves was also performed after in vivo MRI., Results: VA of the TBI mice showed unilateral or bilateral impairment. DBSI of the optic nerves exhibited bilateral involvement. IHC results of the optic nerves revealed axonal loss, myelin injury, axonal injury, and increased cellularity in the optic nerves of the TBI mice. Increased DBSI axon volume, decreased DBSI λ || , and elevated DBSI restricted fraction correlated with decreased SMI-312, decreased SMI-31, and increased DAPI density, respectively, suggesting that DBSI can detect coexisting pathologies in the optic nerves of TBI mice., Conclusion: DBSI provides an imaging modality capable of detecting subclinical changes of indirect TON in TBI mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Lavadi, Sauerbeck, Wallendorf, Kummer, Song and Lin.)