1. Alzheimer's peptide amyloid-β, fragment 22-40, perturbs lipid dynamics
Matthew A Barrett, Marcus Trapp, Wiebke Lohstroh, Tilo Seydel, Jacques Ollivier, Matthias Ballauff, Norbert A Dencher, Thomas Hauß Soft Matter. 2016 Feb 7;12(5):1444-51. doi: 10.1039/c5sm02026c. Epub 2015 Dec 8.
The peptide amyloid-β (Aβ) interacts with membranes of cells in the human brain and is associated with Alzheimer's disease (AD). The intercalation of Aβ in membranes alters membrane properties, including the structure and lipid dynamics. Any change in the membrane lipid dynamics will affect essential membrane processes, such as energy conversion, signal transduction and amyloid precursor protein (APP) processing, and may result in the observed neurotoxicity associated with the disease. The influence of this peptide on membrane dynamics was studied with quasi-elastic neutron scattering, a technique which allows a wide range of observation times from picoseconds to nanoseconds, over nanometer length scales. The effect of the membrane integral neurotoxic peptide amyloid-β, residues 22-40, on the in- and out-of-plane lipid dynamics was observed in an oriented DMPC/DMPS bilayer at 15 °C, in its gel phase, and at 30 °C, near the phase transition temperature of the lipids. Near the phase-transition temperature, a 1.5 mol% of peptide causes up to a twofold decrease in the lipid diffusion coefficients. In the gel-phase, this effect is reversed, with amyloid-β(22-40) increasing the lipid diffusion coefficients. The observed changes in lipid diffusion are relevant to protein-protein interactions, which are strongly influenced by the diffusion of membrane components. The effect of the amyloid-β peptide fragment on the diffusion of membrane lipids will provide insight into the membrane's role in AD.
2. Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: (18)F-florbetapir (AV-45/Amyvid) PET study
Kuan-Yi Wu, Chia-Yih Liu, Cheng-Sheng Chen, Chia-Hsiang Chen, Ing-Tsung Hsiao, Chia-Ju Hsieh, Chin-Pang Lee, Tzu-Chen Yen, Kun-Ju Lin Eur J Nucl Med Mol Imaging. 2016 Jun;43(6):1067-76. doi: 10.1007/s00259-015-3291-3. Epub 2016 Jan 7.
Purpose: The objective of this study was to evaluate the amyloid burden, as assessed by (18)F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients. Methods: The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and (18)F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined. Results: Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative (18)F-florbetapir uptake in all cortical regions, and a significant difference in relative (18)F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects (P < 0.05) and HCs (P < 0.01). Voxel-wise analyses revealed significantly increased relative (18)F-florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas (P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score (r = -0.342, P = 0.010) and memory function (r = -0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity (β = -3.607, t = -2.874, P = 0.006). Conclusion: We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the hypothesis that a higher amyloid burden is associated with a poorer memory performance. We also observed a high prevalence of MCI among elderly depressed patients, and depressed patients with MCI exhibited heterogeneously elevated (18)F-florbetapir retention as compared with depressed patients without MCI. The higher amyloid burden in the aMCI patients suggests that these patients may also be more likely to develop Alzheimer's disease than other patients diagnosed with major depression.
3. The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice
Kendra L Puig, Joshua A Kulas, Whitney Franklin, Sharlene G Rakoczy, Giulio Taglialatela, Holly M Brown-Borg, Colin K Combs Neurobiol Aging. 2016 Apr;40:22-40. doi: 10.1016/j.neurobiolaging.2015.12.021. Epub 2016 Jan 6.
APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Aβ) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Aβ plaque deposition and Aβ 1-40 and Aβ 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression.