β - Secretase: Progress and Open Questions

Martin Citron

Finding inhibitors of Aβ42 generation is a major goal of Alzheimer's disease drug development. Two target protease activities, β-and γ-secretases, were operationally defined more than 10 years ago, but progress in this area has been slow because the actual enzymes were no...

γ -Secretase and Presenilin

Michael S. Wolfe

Because production and deposition of the amyloid-β peptide (Aβ) is intimately linked to the pathogenesis of Alzheimer's disease (AD), the proteases responsible for excising Aβ from the amyloid-β precursor protein (APP), β- and γ-secretases, are considered i...

a-Synuclein Binding Proteins

Cytoplasmic inclusions containing a-synuclein in a filamentous form is present in the degenerating cells of several neurodegenerative diseases, the so-called synucleinopathies among whom Parkinson’s disease is a principal member. Moreover, mutations causing single amino acid substitutions in a-synuc...

A Kinase with a Vision: Role of ERK in the Synaptic Plasticity of the Visual Cortex

Gian Michele Ratto and Tommaso Pizzorusso

We look at these written words with two eyes, their neuronal representations are elabo rated separately in the two retinae and they are conveyed to two separate zones of the thalamus. The segregation in eye specific structures is broken only in the primary visual cortex, where neurons respons...

A Role for Glutamate Transporters in Neurodegenerative Diseases

Davide Trotti

In the mammalian central nervous system (CNS) L-glutamic acid acts as a chemical transmitter of excitatory signals. L-glutamate is released in the synaptic cleft and activates a multitude of highly integrated signaling pathways by binding to an array of iono- and metabotropic glutamate r...

Aβ Metabolism in Cholesterol Enriched Membrane Microdomains

Todd E. Golde and M. Paul Murphy

Aggregation and accumulation of Aβ is a pathological hallmark of the Alzheimer's disease (AD) brain. Studies on cerebrospinal fluid (CSF) from living patients and postmortem control brain tissue show the normal level of Aβ in the brain to be in the low nM range. Biophysical stu...

Aβ Degradation by Endothelin-Converting Enzymes

Elizabeth A. Eckman and Christopher B. Eckman

The abnormal accumulation of β-amyloidloid (Aβ) in the brain is an early and invariant feature of Alzheimer's disease and is believed to play a pivotal role in the etiology and pathogenesis of the disease. The concentration of Aβ is regulated by multiple enzymatic activiti...

alpha-Synuclein Physiology and Membrane Binding

An amphipathic alpha-helical domain in the N-terminus of alpha-synuclein (AS) mediates binding to phospholipid membranes. This domain is structurally similar to the class A2 lipid-binding motif described for the exchangeable apolipoproteins. AS is unstructured in aqueous solution, but shifts to a un...

Alzheimer Disease—A New Beginning, or a Final Exit?

Mark E. Obrenovich, Arun K. Raina, Osamu Ogawa, Craig S. Atwood, Laura Morelli and Mark A. Smith

Today, a new chapter is being written in the book of Alzheimer disease, one that is challenging the longstanding view that adult neurons are incapable of division, remain nonproliferative, and are terminally differentiated. Here, we review the provocative notion that, in Alzheimer diseas...

Alzheimer Disease: A New Beginning or a Final Exit?

Mark E. Obrenovich, Arun K. Raina, Osamu Ogawa, Craig S. Atwood, Laura Morelli and Mark A. Smith

Today, a new chapter is being written in the book of Alzheimer disease, one that is challenging the longstanding view that adult neurons are incapable of division, remain nonproliferative, and are terminally differentiated. Here, we review the provocative notion that, in Alzheimer disease, whole ...

Amyloid β-Protein in Low-Density Membrane Domains

Maho Morishima-Kawashima and Yasuo lhara

Membrane microdomains, which have just been emerging thanks to recent technological progress, may have significant roles in normal cell functions such as adhesion, signaling, and trafficking. We found that a significant amount of amyloid β-protein (Aβ) is located to the cholest...

APP α -Secretase, a Novel Target for Alzheimer Drug Therapy

Shoichi Ishiura, Masashi Asai, Chinatsu Hattori, Nika Hotoda, Beata Szabo, Noboru Sasagawa and Sei-ichi Tanuma

The neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β peptide (Aβ) in plaques in brain tissue (amyloid hypothesis). Mechanisms of Aβ production in the brain have been the subject of considerable interest. Several factors regulate processing o...

Attempts to Restore Visual Function After Optic Nerve Damage in Adult Mammals

Tomomitsu Miyoshi, Takuji Kurimoto and Yutaka Fukuda

Retinal ganglion cells (RGCs) and their axons, i.e., optic nerve (ON) fibers, provide a good experimental model for research on damaged CNS neurons and their functional recovery. After the ON transection most RGCs undergo retrograde and anterograde degeneration but they can be rescued and rege...

Behavioral Recovery of Functional Responses

Lazaros C. Triarhou

Studies in rats have shown that unilateral destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) results in a spontaneous rotational bias to the side ipsilateral to the lesion.¹ With time, spontaneous rotational behavior subsides, but it can still be induce...

Biology and Pathology of the Weaver Mutant Mouse

Lazaros C. Triarhou

The weaver mutant mouse (wv/wv) is characterized by a genetically-induced degeneration of mesostriatal dopamine (DA) neurons. In that sense, it can be viewed as a pathophysiological phenocopy of Parkinsonism and, therefore, an invaluable experimental model for investigating mechanisms...

Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain Ischemia Following Delayed Intravenous Administration of Neurotrophins

William M. Pardridge

The bloodbrain barrier (BBB) is the ratelimiting step in the translation of neurotrophin neuroscience into clinically effective neurotherapeutics. Since neurotrophins do not cross the BBB, these proteins cannot be used for neuroprotection following intravenous administr...

Cell Cycle Activation and Cell Death in the Nervous System

Zsuzsanna Nagy

The discovery of the cell division cycle opened new avenues for the understanding of cancer as well as in the search for therapy. However, the implications of the discovery had a more profound effect on biological research than anticipated at the time. We can now clearly distinguish between the a...

Cell Cycle Activation in Neurons: The Final Exit of Brain Morpho-Dysregulation

Thomas Arendt

Mammalien cells act and react within frameworks of defined cellular programmes such as division, movement, adhesion, differentiation and death, integrating both genetic and epigenetic information. Execution of these programmes, ones activated, are surprisingly stable, even under pathological cond...

Cell Cycle and Chromosome Segregation Defects in Alzheimer’s Disease

Huntington Potter

Despite a common set of hallmark neuropathological lesions and clinical symptoms, Alzheimer’s disease has an apparently complex etiology. The disease can be caused by autosomal dominant mutations in at least three genes (encoding the amyloid precursor protein (APP) and the two presenilins). In ad...

Cell Death in the Nervous System

Kerstin Krieglstein

Programmed cell death is a fundamental and essential process in development and tissue homeostasis of multicellular organisms. About half of all neurons produced during neurogenesis die before the nervous system matures. Failure to kill appropriate cells can lead to severe developmental defect...

Cellular and Molecular Determinants of Glial Scar Formation

Ann Logan and Martin Berry

Many axotomised neurons die and none of their severed axons regenerate after penetrant CNS injury in the adult. Debris and necrotic tissue is phagacytosed by hematogenous macrophages and microglia. The scar is formed by astrocytes interacting with fibrous tissue invading the wound from the...

Chromosome 1 and Other Hotspots for Parkinson’s Disease Genes

The arena of Parkinson’s disease (PD) genetics is becoming more and more crowded with findings emerging from complementary approaches. Classical linkage analyses in families with Mendelian inheritance, affected-pairs analyses in smaller families, and studies in genetically isolated populations are a...

Detrimental and Beneficial Effects of Injury-Induced Inflammation and Cytokine Expression in the Nervous System

Guido Stoll, Sebastian Jander and Michael Schroeter

Lesions in the nervous system induce rapid activation of glial cells and under certain conditions additional recruitment of granulocytes, T-cells and monocytes/macrophages from the blood stream triggered by upregulation of cell adhesion molecules, chemokines and cyto...

Directions for Future Research

Lazaros C. Triarhou

Our groundwork, first, introduced and characterized in detail the weaver mouse as a model of spontaneous progressive dopamine (DA) deficiency similar to Parkinson's disease, and secondly, laid the foundations for the intracerebral transplantation of catecholamine-producing neurons in ...

Do Familial Parkinson’s Disease Genes Share a Common Pathway Involved in the Nigral Degeneration?

Parkinson’ s disease (PD) is the most common progressive movement disorders characterized by resting tremor, cogwheel rigidity, bradykineasi, and impaired postural reflexes with a prevalence of approximately 200/100,0000 among white populations1 and 100/100,000 in Japanese.2 Considering the age at o...