Alzheimer Mechanisms and Therapeutic Strategies

Cell, Год журнала: 2012, Номер 148(6), С. 1204 - 1222

Опубликована: Март 1, 2012

Язык: Английский

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Mitochondria as sensors and regulators of calcium signalling

Nature Reviews Molecular Cell Biology, Год журнала: 2012, Номер 13(9), С. 566 - 578

Опубликована: Авг. 1, 2012

Язык: Английский

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Synaptic Energy Use and Supply

Neuron, Год журнала: 2012, Номер 75(5), С. 762 - 777

Опубликована: Сен. 1, 2012

Neuronal computation is energetically expensive. Consequently, the brain's limited energy supply imposes constraints on its information processing capability. Most brain used synaptic transmission, making it important to understand how provided and by synapses. We describe transmission through presynaptic terminals postsynaptic spines related their consumption, assess which mechanisms normally ensure an adequate of ATP these structures, consider influence plasticity changing state use, explain disruption synapses leads neuropathology. The nervous system consumes a disproportionate fraction resting body's production: in humans only 2% mass, yet uses ∼20% O2 consumed body (Mink et al., 1981Mink J.W. Blumenschine R.J. Adams D.B. Ratio central metabolism vertebrates: constancy functional basis.Am. J. Physiol. 1981; 241: R203-R212PubMed Google Scholar), while retina alone 10% fly's consumption (Laughlin 1998Laughlin S.B. de Ruyter van Steveninck R.R. Anderson J.C. metabolic cost neural information.Nat. Neurosci. 1998; 1: 36-41Crossref PubMed Scholar). relative has increased particularly during evolution from lower primates Scholar; Aiello Wheeler, 1995Aiello L.C. Wheeler P. expensive tissue hypothesis: digestive human primate evolution.Curr. Anthropol. 1995; 36: 199-221Crossref reflecting 3-fold expansion size increase number per cortical neuron (Abeles, 1991Abeles M. Corticonics: Neural Circuits Cerebral Cortex. CUP, Cambridge1991Crossref This greater allocation CNS over millions years underpins our brains' cognitive powers, was made possible higher-quality food intake, along with less expenditure gut locomotion (Aiello Navarrete 2011Navarrete A. Schaik C.P. Isler K. Energetics size.Nature. 2011; 480: 91-93Crossref Scopus (90) What all this for brain, does determine power, high use predispose problems when not supplied at necessary rate? will review most synapses, investigate pre- are optimized maximize minimum cost, provision regulated satisfy energetic needs. then synapse changes development plasticity, between wake sleep states, before relating defects can lead disease. major subcellular processes underlying signaling (Figure 1) been estimated rat cerebral cortex (Attwell Laughlin, 2001Attwell D. Laughlin An budget grey matter brain.J. Cereb. Blood Flow Metab. 2001; 21: 1133-1145Crossref Scholar) (Lennie, 2003Lennie computation.Curr. Biol. 2003; 13: 493-497Abstract Full Text PDF (319) Anatomical data mean cell size, capacitance area membrane, were estimate Na+ that enters produce action potentials thus needs be pumped out again Na+/K+-ATPase, consuming ATP. Similarly, patch-clamp quantification ions entering generate typical currents, also need (for simplicity neurons, rather than ∼85% [Abeles, Scholar], assumed excitatory). ion pumping maintaining potential, biochemical pathways transmitter vesicle recycling, calculated. analysis where suggested electrical consumer brain. Furthermore, largest component transmission. Figure 2A shows predicted distribution across different neocortex, updated earlier Attwell Scholar calculations taking into account fact mammalian neurons based squid axon (Alle 2009Alle H. Roth Geiger J.R. Energy-efficient hippocampal mossy fibres.Science. 2009; 325: 1405-1408Crossref (110) Carter Bean, 2009Carter B.C. Bean B.P. Sodium entry neurons: incomplete inactivation reduced efficiency fast-spiking neurons.Neuron. 64: 898-909Abstract (56) Sengupta 2010Sengupta B. Stemmler Niven J.E. Action potential varies among types vertebrates invertebrates.PLoS Comput. 2010; 6: e1000840Crossref (6) Harris Attwell, 2012Harris J.J. energetics white matter.J. 2012; 32: 356-371Crossref (39) These predict mediating (including glutamate accumulation vesicles) consume 55% total potentials, glia. equivalent 41% if housekeeping tasks like synthesis molecules organelle trafficking, 25% percentage may even larger cortex, In contrast, gray matter, mainly because 80-fold density (Harris various contributing 2B) reversing movements generating responses great majority (at excitatory synapses: inhibitory much reverse Cl− fluxes chloride reversal close [Howarth 2010Howarth C. Peppiatt-Wildman C.M. associated cerebellum.J. 30: 403-414Crossref (23) Scholar]). 2C compares dendrites soma, axons, glia mitochondria observed locations Wong-Riley, 1989Wong-Riley M.T.T. Cytochrome oxidase: endogenous marker neuronal activity.Trends 1989; 12: 94-101Abstract (763) Scholar. location reflects well currents 2A). axons those areas, perhaps implying there some process unaccounted (possibly trafficking: Verstreken 2005Verstreken Ly C.V. Venken K.J. Koh T.W. Zhou Y. Bellen H.J. Synaptic critical mobilization reserve pool vesicles Drosophila neuromuscular junctions.Neuron. 2005; 47: 365-378Abstract (315) astrocyte substantially astrocytes, possibly astrocytes more glycolytic neurons. Since such large energy, we might expect have function they transmit minimizing order reduce circuits. Based idea, following sections present "energetic design principles" spines. First, needed single synapse, as prelude explaining transmitted maximized cost. input considered sequence time intervals, Δt, either or arrive axon, e.g., signifying presence absence stimulus 3A , Δt smallest interval represent information, set refractory period potential). If spike firing rate S, probability arriving any given s = SΔt (with 0 < 1), assume no correlation occurrence arrives train (Shannon, 1948Shannon C.E. A mathematical theory communication.Bell Syst. Tech. 1948; 27: 379-423Crossref Dayan Abbott, 2001Dayan Abbott L. Theoretical Neuroscience. MIT Press, Cambridge, MA2001Google Scholar, Equation 4.4; Levy Baxter, 1996Levy W.B. Baxter R.A. Energy efficient codes.Neural 1996; 8: 531-543Crossref 2.1)Iinput(s)=−s⋅log2(s)–(1−s)⋅log2(1−s)(1) bits 3A). 0.5, S 1/(2Δt), i.e., half maximum rate. ∼200 Hz 2.5 ms, practice vivo this, around 4 Perge 2009Perge J.A. Koch Miller R. Sterling Balasubramanian V. How optic nerve allocates space, capacity, information.J. 29: 7917-7928Crossref To difference, that, fact, maximizes ratio (rather maximizing coding capacity). They showed (and glia) r-fold higher producing inactive, (s∗) would capacity. Their implies factor, r, spiking increases s∗ via equationr=log2(s∗)log2(1−s∗),(2) below. Applying similar principles surprising conclusion release fails often—just seen flow consumes. For site (e.g., orange 3), each released p, p 1 lost because, current tells definitely (ignoring spontaneous below), occurs due occurring alternatively failing evoke release. amount passing measured so-called mutual (EPSCs) us about (APs), calculated (see 3B legend) asIm(EPSCs;APs)=Iinput(s)+(1−s)⋅log2((1−s)(1−p⋅s))+s⋅(1−p)⋅log2(s⋅(1−p)(1−p⋅s))(3) within Δt. sum last two terms negative decreases below defined 1. 3 plotted values s, normalized incoming stream above, show incident synapse. transfer 2001Balasubramanian Kimber Berry 2nd, M.J. Metabolically processing.Neural 799-815Crossref (49) 3C emerging consumed, take being proportional release, s·p figure legend). As example physiological 0.01 (implying Hz) 0.25, states 32 bits/s 6.8 transmitted, (Evesicle 1.64 × 105 released), achieved S·p·Evesicle ATP/s. Thus, typically costs ∼24,000 bit, Increasing bits/s, 20,500 ATP/bit. Both (Figures 3C). Why do 0.25–0.5 Scholar)? section low used. It allows wide dynamic range, correlated inputs, storage (Zador, 1998Zador Impact unreliability neurons.J. Neurophysiol. 79: 1219-1229PubMed Goldman, 2004Goldman M.S. Enhancement failures.Neural 2004; 16: 1137-1162Crossref (22) Varshney 2006Varshney L.R. Sjöström P.J. Chklovskii Optimal noisy under resource constraints.Neuron. 2006; 52: 409-423Abstract (27) However, aspects benefit probability. considering neuron, existence multiple sites (usually onto spines), (as brown results below). Second, impinging dendritic tree matched output convey failures should occur (Levy 2002Levy quantal failures.J. 2002; 22: 4746-4755PubMed Taking first issue several (N) one cell, define response whenever receives least current. (Because determining arrival EPSCs train, amplitude EPSC immaterial [although affects cell].) ignore noise variability evoked vesicles, received (i.e., see byIm=Iinput(s)+(1−s)⋅log2((1−s)[1−s+s⋅(1−p)N])+s⋅(1−p)N⋅log2(s⋅(1−p)N[1−s+s⋅(1−p)N])(4) sites, N, 2001Zador A.M. connectivity computation.Nat. 4: 1157-1158Crossref (4) but often 1, 6 pyramidal interneuron (Deuchars Thomson, 1995Deuchars Thomson Innervation burst spiny interneurons cells deep layers somatomotor cortex: paired intracellular recordings biocytin filling.Neuroscience. 69: 739-755Crossref (47) 4–6 stellate (Markram 1997Markram Lübke Frotscher Sakmann Physiology anatomy connections thick tufted neurones developing neocortex.J. 1997; 500: 409-440Crossref Silver 2003Silver Feldmeyer High-probability uniquantal barrel cortex.Science. 302: 1981-1984Crossref (108) ∼6 CA1 (Larkman 1997Larkman A.U. Jack Stratford Quantal vitro low-frequency depression.J. 505: 457-471Crossref (38) multiplicity parallel, usually spines, exist stable face spine turnover (Xu 2007Xu H.-T. Pan F. Yang G. Gan W.-B. Choice cranial window type imaging cortex.Nat. 2007; 10: 549-551Crossref (149) 3D (black lines) axonal numbers same p), ∼4 ms (higher give curves shape). Having (N > receiving reliability so postsynaptically (de 1996de graded-potential synapses.Nature. 379: 642-645Crossref (116) Manwani Koch, 2001Manwani Detecting estimating signals unreliable information-theoretic analysis.Neural 1-33Crossref Zador, shown black lines 3E, N longer case maximal 1; indeed, highest very low. example, 0.25 transmits 60% (since 1/4 released). Surprisingly, preceding predicts greatest (information transmitted/energy used) convergent zero 3E). realistic result obtained recognized experience miniature m Δt), produces effect indistinguishable vesicle. becomesIm=Iinput(s)+(1−m)⋅{(1−s)⋅log2((1−s)[1−s+s⋅(1−p)N])+s⋅(1−p)N⋅log2(s⋅(1−p)N[1−s+s⋅(1−p)N])}+(1−s)⋅m⋅log2{(1−s)⋅m[m+s⋅(1−m)⋅(1−(1−p)N)]}+s⋅[1−(1−p)N⋅(1−m)]⋅log2{s⋅[1−(1−p)N⋅(1−m)][m+s⋅(1−m)⋅(1−(1−p)N)]}(5) transmittable (red 3D) driven drops off 3E), frequency becomes comparable (s interval, firing), 1.2 (Dani 2005Dani V.S. Chang Q. Maffei Turrigiano G.G. Jaenisch Nelson Reduced activity shift balance excitation inhibition mouse model Rett syndrome.Proc. Natl. Acad. Sci. USA. 102: 12560-12565Crossref (265) 0.003 creates optimal range 0.05–0.25, depending converging cell. 3E makes neuron. Strikingly, just relationship reported Hardingham 2010Hardingham N.R. Read J.C.A. Trevelyan A.J. J.J.B. Bannister N.J. reveals efficacy 1441-1451Crossref (17) (their 7C) Branco 2008Branco T. Staras Darcy Goda Local sets synapses.Neuron. 2008; 59: 475-485Abstract (91) 2D) ∼0.7 declining ∼0.25–0.4 ∼0.1 ∼10 sites. While quantitative differences measurements (in particular sites), provides experimental confirmation unexpected inverse above predicts. make found experimentally)—perhaps provide Scholar)—more having (This conclusion, section, independent [provided quantity sites] depend exactly receptor subunits expressed synapses.) although appear intuitively wasteful, allow bit minimized. Another argument depends 8,000 (Braitenberg Schüz, 1998Braitenberg Schüz Cortex: Statistics Geometry Connectivity.Second Edition. Springer, Berlin1998Crossref pointed wasted transmitting cannot passed waste. With assumptions fire energy-limited (Equation 2) cell's defines failure by1−p=(14)Iinput(s∗)(6) probability, Iinput 2. ideal inputs (if few hundred synapses). 3F vary spiking. 2, r 150 approximately 0.2. Neuro

Язык: Английский

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Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

International Journal of Molecular Sciences, Год журнала: 2018, Номер 19(3), С. 833 - 833

Опубликована: Март 13, 2018

The biological effects of cannabinoids, the major constituents ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. CB1R is prominent subtype in central nervous system (CNS) has drawn great attention as a potential therapeutic avenue several pathological conditions, including neuropsychological disorders neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways exert profound at peripheral sites. Although have potential, their psychoactive largely limited use clinical practice. In this review, we briefly summarized our knowledge endocannabinoid system, focusing on CNS, with emphasis recent breakthroughs field. We aim to define roles modulation signaling association pathophysiological conditions. believe that significance masked adverse here alternative strategies discussed take advantage cannabinoids.

Язык: Английский

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The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

Neuron, Год журнала: 2014, Номер 82(4), С. 756 - 771

Опубликована: Май 1, 2014

Язык: Английский

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Autophagy and apoptosis dysfunction in neurodegenerative disorders

Progress in Neurobiology, Год журнала: 2013, Номер 112, С. 24 - 49

Опубликована: Ноя. 6, 2013

Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. encompasses pathways that target long-lived cytosolic proteins damaged organelles. It involves a sequential set events including double membrane formation, elongation, vesicle maturation finally delivery targeted materials lysosome. Apoptotic cell death is best described through its morphology. characterized by rounding, blebbing, cytoskeletal collapse, cytoplasmic condensation, fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, formation membrane-enveloped apoptotic bodies, rapidly phagocytosed macrophages or neighboring cells. Neurodegenerative disorders becoming increasingly prevalent, especially in Western societies, with larger percentage members living an older age. They have be seen not only as health problem, but since they care-intensive, also carry significant economic burden. Deregulation autophagy plays pivotal role etiology and/or progress many these diseases. Herein, we briefly review latest findings indicate involvement neurodegenerative We provide brief introduction focusing on mitochondria lysosomes. then highlight pathophysiology common like Alzheimer's diseases, Parkinson's disease, Huntington's disease Amyotrophic lateral sclerosis. Then, describe functions brain homeostasis, context aforementioned disorders. Finally, discuss different ways modulation may employed for therapeutic intervention during

Язык: Английский

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Cargo recognition and degradation by selective autophagy

Nature Cell Biology, Год журнала: 2018, Номер 20(3), С. 233 - 242

Опубликована: Фев. 14, 2018

Язык: Английский

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Mitochondrial dynamics and inheritance during cell division, development and disease

Nature Reviews Molecular Cell Biology, Год журнала: 2014, Номер 15(10), С. 634 - 646

Опубликована: Сен. 17, 2014

Язык: Английский

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Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Molecular Neurodegeneration, Год журнала: 2020, Номер 15(1)

Опубликована: Май 29, 2020

Abstract Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss neurons in brain. Under microscope, neuronal accumulation abnormal tau proteins and amyloid plaques are two pathological hallmarks affected brain regions. Although detailed mechanism pathogenesis AD still elusive, a large body evidence suggests that damaged mitochondria likely play fundamental roles AD. It believed healthy pool not only supports activity providing enough energy supply other related mitochondrial functions neurons, but also guards minimizing oxidative damage. In this regard, exploration multitude mechanisms altered constitutes novel promising therapeutic targets for disease. review, we will summarize recent progress underscores essential role dysfunction discuss underlying with focus on structural functional integrity including biogenesis dynamics, axonal transport, ER-mitochondria interaction, mitophagy proteostasis.

Язык: Английский

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Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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