A New Mint1 Isoform, but Not the Conventional Mint1, Interacts with the Small GTPase Rab6

Small GTPases of the Rab family are important regulators of a large variety of different cellular functions such as membrane organization and vesicle trafficking. They have been shown to play a role in several human diseases. One prominent member, Rab6, is thought to be involved in the development of Alzheimer’s Disease, the most prevalent mental disorder worldwide. Previous studies have shown that Rab6 impairs the processing of the amyloid precursor protein (APP), which is cleaved to β-amyloid in brains of patients suffering from Alzheimer’s Disease. Additionally, all three members of the Mint adaptor family are implied to participate in the amyloidogenic pathway. Here, we report the identification of a new Mint1 isoform in a yeast two-hybrid screening, Mint1 826, which lacks an eleven amino acid (aa) sequence in the conserved C-terminal region. Mint1 826, but not the conventional Mint1, interacts with Rab6 via the PTB domain. This interaction is nucleotide-dependent, Rab6-specific and influences the subcellular localization of Mint1 826. We were able to detect and sequence a corresponding proteolytic peptide derived from cellular Mint1 826 by mass spectrometry proving the absence of aa 495–505 and could show that the deletion does not influence the ability of this adaptor protein to interact with APP. Taking into account that APP interacts and co-localizes with Mint1 826 and is transported in Rab6 positive vesicles, our data suggest that Mint1 826 bridges APP to the small GTPase at distinct cellular sorting points, establishing Mint1 826 as an important player in regulation of APP trafficking and processing

Structural aspects and physiological consequences of APP/APLP trans-dimerization

The amyloid precursor protein (APP) is one of the key proteins in Alzheimer’s disease (AD), as it is the precursor of amyloid β (Aβ) peptides accumulating in amyloid plaques. The processing of APP and the pathogenic features of especially Aβ oligomers have been analyzed in detail. Remarkably, there is accumulating evidence from cell biological and structural studies suggesting that APP and its mammalian homologs, the amyloid precursor-like proteins (APLP1 and APLP2), participate under physiological conditions via trans-cellular dimerization in synaptogenesis. This offers the possibility that loss of synapses in AD might be partially explained by dysfunction of APP/APLPs cell adhesion properties. In this review, structural characteristics of APP trans-cellular interaction will be placed critically in context with its putative physiological functions focusing on cell adhesion and synaptogenesis

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days

Stability and Change of Personality Across the Life Course: The Impact of Age and Major Life Events on Mean-Level and Rank-Order Stability of the Big Five

Does personality change across the entire life course, and are those changes due to intrinsic maturation or major life experiences? This longitudinal study investigated changes in the mean levels and rank order of the Big Five personality traits in a heterogeneous sample of 14,718 Germans across all of adulthood. Latent change and latent moderated regression models provided four main findings: First, age had a complex curvilinear influence on mean levels of personality. Second, the rank-order stability of Emotional Stability, Extraversion, Openness, and Agreeableness all followed an inverted U-shaped function, reaching a peak between the ages of 40 and 60, and decreasing afterwards, whereas Conscientiousness showed a continuously increasing rank-order stability across adulthood. Third, personality predicted the occurrence of several objective major life events (selection effects) and changed in reaction to experiencing these events (socialization effects), suggesting that personality can change due to factors other than intrinsic maturation.. - Fourth, when events were clustered according to their valence, as is commonly done,. - effects of the environment on changes in personality were either overlooked or. - overgeneralized. In sum, our analyses show that personality changes throughout the life. - span, but with more pronounced changes in young and old ages, and that this change is. - partly attributable to social demands and experiences

Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA

Proteolytic cleavage of the amyloid precursor protein (APP) byα-, β- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic A{beta} production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting A{beta} production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD

Do axonal defects in tau and amyloid precursor protein transgenic animals model axonopathy in Alzheimer's disease?

The subcellular localization of organelles, mRNAs and proteins is particularly challenging in neurons. Owing to their extended morphology, with axons in humans exceeding a meter in length, in addition to which they are not renewed but persist for the entire lifespan, it is no surprise that neurons are highly vulnerable to any perturbation of their sophisticated transport machinery. There is emerging evidence that impaired transport is not only causative for a range of motor disorders, but possibly also for Alzheimer's disease (AD) and related neurodegenerative disorders. Support for this hypothesis comes from transgenic animal models. Overexpression of human tau and amyloid precursor protein (APP) in mice and flies models the key hallmark histopathological characteristics of AD, such as somatodendritic accumulation of phosphorylated forms of tau and β-amyloid (Aβ) peptide-containing amyloid plaques, as well as axonopathy. The latter has also been demonstrated in mutant mice with altered levels of Alzheimer-associated genes, such as presenilin (PS). In Approducing APP transgenic mice, axonopathy was observed before the onset of plaque formation and tau hyperphosphorylation. In human AD brain, an axonopathy was revealed for early but not late Braak stages. The overall picture is that key players in AD, such as tau, APP and PS, perturb axonal transport early on in AD, causing impaired synaptic plasticity and reducing survival rates. It will be challenging to determine the molecular mechanisms of these different axonopathies, as this might assist in the development of new therapeutic strategies