Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβ and its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβ may directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβ and AβPP addressing the question of how Aβ can access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβ triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on Aβ interaction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes. bipolar disorder | endophenotypes | circadian rhythms | actigraphy | behavior Q uantitative sleep and activity measures are hypothesized to be endophenotypes for bipolar disorder (BP). Disturbance of sleep and circadian activity typically precedes and may precipitate the initial onset of BP (1, 2). Decreased sleep and increased activity occur before and during manic and hypomanic episodes. Conversely, increased sleep and decreased activity characterize BP-depression. Extreme diurnal variation in mood features prominently in both mania and depression, whereas shifts in circadian phase (the time within the daily activity cycle at which periodic phenomena such as bed time or awakening occur) can induce mania and ameliorate symptoms of BP-depression (3).Twin studies have identified multiple heritable sleep and activity phenotypes, including sleep duration, sleep quality, phase of activity preference and sleep pattern, and sleep architecture variables [e.g., the amount of slow wave and rapid eye movement (REM) sleep (4) and polysomnography profiles during non-REM sleep (5)]. Euthymic BP individuals, compared with healthy controls, display trait-like alterations in several such phenotypesfor example, sleep time and time in bed, sleep onset latency, and periods of being awake after sleep onset (6). However, no prior investigations have assayed the heritability of such phenotypes in BP individuals and their relatives.We report here the delineation of sleep and activity BP endophenotypes through investigations of 26 pedigrees (n = 558) ascertained for severe BP (BP-I), from the genetically related populations of the Central Valley of Costa Rica (CR) and Antioquia, Colombia (CO) (7-9). Pedigrees ascertained for multiple cases of severe BP (BP-I) should be enriched for extreme values of quantitative traits that are BP endophenotypes, enhancing their utility for genetic mapping studies of such phenotypes. Additionally, su...

BackgroundDiurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype (“larks” and “owls”), clock properties measured in human fibroblasts correlated with extreme diurnal behavior.Methodology/Principal FindingsIn this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer.Conclusions/SignificanceWe conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness.

Human aging is accompanied by dramatic changes in daily sleepwake behavior: Activity shifts to an earlier phase, and the consolidation of sleep and wake is disturbed. Although this daily circadian rhythm is brain-controlled, its mechanism is encoded by cellautonomous circadian clocks functioning in nearly every cell of the body. In fact, human clock properties measured in peripheral cells such as fibroblasts closely mimic those measured physiologically and behaviorally in the same subjects. To understand better the molecular mechanisms by which human aging affects circadian clocks, we characterized the clock properties of fibroblasts cultivated from dermal biopsies of young and older subjects. Fibroblast period length, amplitude, and phase were identical in the two groups even though behavior was not, thereby suggesting that basic clock properties of peripheral cells do not change during aging. Interestingly, measurement of the same cells in the presence of human serum from older donors shortened period length and advanced the phase of cellular circadian rhythms compared with treatment with serum from young subjects, indicating that a circulating factor might alter human chronotype. Further experiments demonstrated that this effect is caused by a thermolabile factor present in serum of older individuals. Thus, even though the molecular machinery of peripheral circadian clocks does not change with age, some age-related circadian dysfunction observed in vivo might be of hormonal origin and therefore might be pharmacologically remediable.chronobiology | peripheral oscillators | human behavior C ircadian clocks possess an endogenous periodicity of about 24 h and play a key role in physiological adaptation to the solar day for all living organisms, from cyanobacteria and fungi (1) to insects (2) and mammals (3). Circadian clocks influence nearly all aspects of physiology and behavior, including sleepwake cycles, body temperature, and the function of many organs (3). During normal aging, clock function is attenuated, with consequences both for health and quality of life. Older individuals have an earlier phase of everyday activity compared with the young (4). Not only is the consolidation of sleep and wake dramatically reduced (5, 6), but overall circadian amplitude of hormones and body temperature are lower (7,8), and many agingassociated sleep-wake pathologies have been reported (9-11). As a result, one in five healthy older individuals reports taking sleep medications regularly (9). In cases of pathological aging, chronobiological disturbance is even more acute: Huntington disease, Parkinson disease, and Alzheimer's disease are all associated with profound alterations in sleeping patterns (10-12). These effects of aging on circadian rhythms-diminished circadian amplitude, earlier phase, shorter circadian period, and desynchronization of rhythms in peripheral organs-have been observed widely in several species of mammals (7,13,14). Paradoxically, however, even though the behavioral phase is earlier in aged humans, m...

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