Alzheimer therapy with passive immunization using the antibody NT4X in Tg4-42hom mice

Aβ4-42 is one of the major variants of beta-amyloid (Aβ) in the Alzheimer brain and one of the earliest to appear in the development of the disease. It shows an increased aggregation tendency and toxicity. Furthermore it has been shown previously, that Aβ4-42 also affects brain functions and induces cognitive impairments in vivo after intraventricular injection to the brain of wildtype mice and in Tg4-42 mice. These mice carry a transgene for an enhanced expression of Aβ4-42 and develop a severe neuron loss in the CA1 region of the hippocampus that correlates with age-dependent memory deficits. Nevertheless, Aβ4-42 has not been considered as a therapeutic target yet. This study analyzes the progression of cognitive deficits in the brain of Tg4-42 mice to detect the best time to start a treatment. It then demonstrates that passive immunization with the antibody NT4X reacting with the free N-terminus of Aβ4-x and AβpE3-X but not with Aβ1-x significantly attenuates neuron loss in the hippocampus of Tg4-42 mice and rescues spatial reference memory deficits. For the first time it could be demonstrated that a preventive therapy with NT4X, which has previously been proven to rescue the toxicity of oligomeric Aβ4-42 in vitro, has therapeutically beneficial effects in an Alzheimer mouse model in vivo, which emphasizes the meaning of Aβ4-42 as a possible target in the treatment of Alzheimer’s disease.2017-07-1

A helical inner scaffold provides a structural basis for centriole cohesion

International audienceThe ninefold radial arrangement of microtubule triplets (MTTs) is the hallmark of the centriole, a conserved organelle crucial for the formation of centrosomes and cilia. Although strong cohesion between MTTs is critical to resist forces applied by ciliary beating and the mitotic spindle, how the centriole maintains its structural integrity is not known. Using cryo-electron tomography and subtomogram averaging of centrioles from four evolutionarily distant species, we found that MTTs are bound together by a helical inner scaffold covering ~70% of the centriole length that maintains MTTs cohesion under compressive forces. Ultrastructure Expansion Microscopy (U-ExM) indicated that POC5, POC1B, FAM161A, and Centrin-2 localize to the scaffold structure along the inner wall of the centriole MTTs. Moreover, we established that these four proteins interact with each other to form a complex that binds microtubules. Together, our results provide a structural and molecular basis for centriole cohesion and geometry

A helical inner scaffold provides a structural basis for centriole cohesion

The ninefold radial arrangement of microtubule triplets (MTTs) is the hallmark of the centriole, a conserved organelle crucial for the formation of centrosomes and cilia. Although strong cohesion between MTTs is critical to resist forces applied by ciliary beating and the mitotic spindle, how the centriole maintains its structural integrity is not known. Using cryo–electron tomography and subtomogram averaging of centrioles from four evolutionarily distant species, we found that MTTs are bound together by a helical inner scaffold covering ~70% of the centriole length that maintains MTTs cohesion under compressive forces. Ultrastructure Expansion Microscopy (U-ExM) indicated that POC5, POC1B, FAM161A, and Centrin-2 localize to the scaffold structure along the inner wall of the centriole MTTs. Moreover, we established that these four proteins interact with each other to form a complex that binds microtubules. Together, our results provide a structural and molecular basis for centriole cohesion and geometry