Biology subjects

Kanekiyo, T.

Publications and source records attributed to Kanekiyo, T..

3 recordsLinked to original sources

bioRxiv2021

Cryo-EM structure of lipid embedded human ABCA7 at 3.6 &Aring resolution

Phospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of the underlying substrate interactions and transport mechanisms remain poorly resolved at the molecular level. Here we report cryo-EM structures of lipid-embedded human ABCA7 in an open state and a nucleotide-bound, closed state at resolutions between 3.6-4.0 [A]. The former reveals an ordered patch of bilayer lipids traversing the transmembrane domain (TMD), while the latter reveals a lipid-free, closed TMD with a small extracellular opening. These structures offer a structural framework for both substrate entry and exit from the ABCA7 TMD and highlight conserved rigid-body motions that underlie the associated conformational transitions. Combined with functional analysis and molecular dynamics (MD) simulations, our data also shed light on lipid partitioning into the ABCA7 TMD and localized membrane perturbations that underlie ABCA7 function and have broader implications for other ABCA family transporters.

biophysics↗

bioRxiv2020

APOE2 promotes longevity independent of Alzheimer's disease

ObjectiveAlthough apolipoprotein E (APOE) allele associates with longevity, its mechanism is not understood. The protective effects of APOE2 and the deleterious effects of APOE4 on Alzheimers disease (AD) risk may confound APOE effects on longevity. MethodsWe analyzed a large number of subjects from the National Alzheimers Coordinating Center (NACC), and animal models expressing human apoE isoforms in the absence of AD. ResultsClinically, the APOE2 allele was associated with longer lifespan, while APOE4 associated with shorter lifespan, compared to the common APOE3 allele. This effect was also seen irrespective of clinical AD status, and in subjects with little amyloid pathology or after adjustment for AD-related pathologies. In animal studies, apoE2-TR mice also exhibited longer lifespan, while apoE4 showed some trends of shorter lifespan. Notably, old apoE2-TR mice kept activity measured by open field assay, associated with longer lifespan. Evidence of preserved activity in APOE2 carrier was also obtained in clinical records. In animal studies, higher levels of apoE2 in brain and plasma were correlated with activity. Moreover, lower levels of total cholesterol in the brain and higher levels of high-density lipoprotein cholesterol and triglycerides in the plasma of apoE2-TR mice were associated with apoE levels and more activity. InterpretationAPOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of apoE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

neuroscience↗

bioRxiv2020

Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimers mouse model

We demonstrate that mitochondrial respiratory chain complex I is an important small molecule druggable target in Alzheimers Disease (AD). Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 mice, a translational model of AD. Treatment of APP/PS1 mice with complex I inhibitor after the onset of AD-like neuropathology improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human AMP-AD transcriptomic data demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

neuroscience↗