Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau.

Abstract

TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPβ1, CR3) associated with Alzheimer's disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.e., hyperphosphorylation and increased tauopathy spreading) were unexpectedly increased in MAPTP301S;Tyrobp-/- mice despite the improved learning behavior and synaptic function relative to controls with normal levels of TYROBP. Notably, levels of complement cascade initiator C1q were reduced in MAPTP301S;Tyrobp-/- mice, consistent with the prediction that C1q reduction exerts a neuroprotective effect. These observations suggest a model wherein TYROBP-KO-(knock-out)-associated reduction in C1q is associated with normalized learning behavior and electrophysiological properties in tauopathy model mice despite a paradoxical evolution of biomarker signatures usually associated with neurological decline.

• Authors: Mickael Audrain, Jean-Vianney Haure-Mirande, Minghui Wang, Soong Ho Kim, Tomas Fanutza, Paramita Chakrabarty, Paul Fraser, Peter H St George-Hyslop, Todd E Golde, Robert D Blitzer, Eric E Schadt, Bin Zhang, Michelle E Ehrlich, Sam Gandy
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 24 Issue 9 Pg. 1383-1397 (09 2019) ISSN: 1476-5578 [Electronic] England
• PMID: 30283031 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Amyloid beta-Protein Precursor
• Membrane Proteins
• TYROBP protein, human
• Tyrobp protein, mouse
• tau Proteins
• Complement C1q

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism, physiology)
• Alzheimer Disease (genetics, metabolism, physiopathology)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Animals, Genetically Modified
• Brain (metabolism)
• Complement C1q (metabolism, physiology)
• Disease Models, Animal
• Humans
• Membrane Proteins (genetics, metabolism, physiology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Microglia (metabolism)
• Phenotype
• Phosphorylation
• Plaque, Amyloid (metabolism)
• Tauopathies (genetics)
• tau Proteins (metabolism)