A Computational Approach in the Systematic Search of the Interaction Partners of Alternatively Spliced TREM2 Isoforms.

Alzheimer's disease is the most common form of dementia, characterized by the pathological accumulation of amyloid-beta (Aß) plaques and tau neurofibrillary tangles. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized as playing a central role in Aß clearance and microglia activation in AD. The TREM2 gene transcriptional product is alternatively spliced to produce three different protein isoforms. The canonical TREM2 isoform binds to DAP12 to activate downstream pathways. However, little is known about the function or interaction partners of the alternative TREM2 isoforms. The present study utilized a computational approach in a systematic search for new interaction partners of the TREM2 isoforms by integrating several state-of-the-art structural bioinformatics tools from initial large-scale screening to one-on-one corroborative modeling and eventual all-atom visualization. CD9, a cell surface glycoprotein involved in cell-cell adhesion and migration, was identified as a new interaction partner for two TREM2 isoforms, and CALM, a calcium-binding protein involved in calcium signaling, was identified as an interaction partner for a third TREM2 isoform, highlighting the potential role of cell adhesion and calcium regulation in AD.

Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy.

BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1-/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1-/-, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.

TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.

BACKGROUND: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular ß-amyloid (Aß) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. RESULTS: Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. CONCLUSIONS: Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aß and tau pathologies.

Regulatory region genetic variation is associated with FYN expression in Alzheimer's disease.

Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau, are a key pathologic feature of Alzheimer's disease (AD). Tau phosphorylation is under the control of multiple kinases and phosphatases, including Fyn. Previously, our group found an association between 2 regulatory single nucleotide polymorphisms in the FYN gene with increased tau levels in the cerebrospinal fluid. In this study, we hypothesized that Fyn expression in the brain is influenced by AD status and genetic content. We found that Fyn protein, but not messenger RNA, levels were increased in AD patients compared to cognitively normal controls and are associated with regulatory region single nucleotide polymorphisms. In addition, the expression of the FYN 3'UTR can decrease expression in multiple cell lines, suggesting this regulatory region plays an important role in FYN expression. Taken together, these data suggest that FYN expression is regulated according to AD status and regulatory region haplotype, and genetic variants may be instrumental in the development of neurofibrillary tangles in AD and other tauopathies.