Current Genomics

ISSN: 1389-2029

Current Genomics
Volume 8, Number 8, December 2007

Contents

New Advances in Alzheimer's Disease: From Biology to Therapy
Guest Editor: Giuseppina Tesco


Editorial Pp. 484-485


Advances on the Understanding of the Origins of Synaptic Pathology in AD Pp. 486-508
P.N. Lacor
[Abstract]


The Basic Biology of BACE1: A Key Therapeutic Target for Alzheimer’s Disease Pp. 509-530
S.L. Cole and R. Vassar
[Abstract]


Structural and Functional Determinants of γ-Secretase, an Intramembrane Protease Implicated in Alzheimer’s Disease Pp. 531-549
P.C. Fraering
[Abstract]


Current Therapeutic Options for Alzheimer’s Disease Pp. 550-558
A. Lleó
[Abstract]




Abstracts


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Editorial: New Advances in Alzheimer's Disease: From Biology to Therapy

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in the loss of memory and cognitive function, and eventually dementia. AD is the most common cause of dementia and the eighth leading cause of death. Increasing age is the greatest risk factor for AD. Under the age of 65 the disease is rare, but it increases dramatically: the disease affects one in 10 individuals over age of 65 and nearly half the population over age of 85. Some 4.5 million individuals in the United States have Alzheimer's disease [1, 2]. Scientists estimate that as the population continues to age and baby boomers reach retirement age and beyond, this number will triple by the year 2050. With this expected increase in the prevalence of AD there will be an increase in the financial burden caused by this condition. Thus, therapies aimed at the prevention and the treatments of AD are desperately needed. This issue of Current Genomics is dedicated to the most recent advances in AD research, which began 100 years ago when the disease was first described.

A key neuropathological event in AD is the cerebral accumulation of an ~4kDa peptide termed Aβ, the principle component of senile plaques. Amyloid plaques are formed by aggregates of amyloid-β-peptides, 37-43 amino-acid fragments (predominantly Aβ40 and Aβ42) derived by serial proteolysis of the amyloid precursor protein (APP) by β- and γ-secretase. APP more commonly undergoes a non-amyloidogenic processing by α-secretase that cleaves in the middle of the β-amyloid domain [3]. β-secretase has been identified as a novel membrane-tethered member of the aspartyl proteases, termed BACE [4, 5], while candidate α-secretases include ADAM 9, 10 and 17 (TACE, tumor necrosis factor-α converting enzyme) [6, 7]. Recent findings have shown that γ-secretase is a complex of four proteins including presenilin, nicastrin/Aph2, Aph1 and Pen-2 [8].

A central role for Aβ in AD pathogenesis is supported by studies of human genetics and data derived from both in vitro and in vivo models. In this issue of Current Genomics, Dr. Lacor reviews the findings that had led to development of the β-amyloid hypothesis, which states that Aβ accumulation is the initial step of a cascade of events starting with dysfunction of synaptic transmission and evolving in the degeneration of neuronal cells. Aβ can exist in a variety of different forms, including monomers, oligomers, protofibrils and fibrils. Dr. Lacor clearly discusses the toxicity of the different Aβ forms focusing on the synaptic toxicity of oligomeric species. These soluble toxins would account for the poor correlation between the number of amyloid plaques and disease progression, and could provide a unifying mechanism for AD pathogenesis.

Since β-secretase processing of APP is the initial step of Aβ generation, BACE is an important target for therapeutic intervention. Drs. Cole and Vassar, who discovered BACE in 1999, review in this issue the biology of BACE with emphasis on its role in normal and disease conditions. Increasing evidence show that BACE is a stress-induced protease, which is upregulated in the brains of AD subjects, following experimental stroke and head trauma among other conditions. In addition to APP, other transmembrane proteins are processed by BACE raising the question of whether BACE inhibition could lead to serious side effects. The fact that BACE null mice are viable and fertile, and are apparently normal, at least early in life, suggests that the inhibition of BACE still represents a primary target for the treatment of AD.

Gamma-secretase cleavage follows β-secretase processing of APP and results in the production of Aβ. The inhibition of γ-secretase is another important target for anti-Aβ therapies. Gamma secretase activity requires the assembly of four proteins including presenilin, nicastrin/Aph2, Aph1 and Pen-2. In this issue Dr. Fraering reviews the role of each components in the regulation of γ-secretase activity. Furthermore, he discusses the most recent findings on the structure of γ-secretase. Electron microscopy (EM) and single particle image analysis of purified γ-secretase complex revealed a globular structure with a low-density central (and possibly water-containing) intramembrane chamber. Further structural studies are required to fully understand how γ-secretase cleaves its substrates within the transmembrane domain. These studies will also help to develop γ-secretase inhibitors or modulators able to prevent Aβ generation without affecting the processing of other vital γ-secretase substrates [9].

Dr. Lleo’s article reviews the therapies currently available to the clinical neurologist for the treatment of subjects affected by AD. Unfortunately these treatments, acetylcholinesterase inhibitors and memantine, an NMDA antagonist, have only modest effects on the symptoms without affecting the progression of the disease. However, the advances in basic research reviewed in this special issue may facilitate the development of more effective drugs e.g. BACE and γ-secretase inhibitors as well as therapies aimed to increase the clearance of Aβ toxic species.

References
[1] Mayeux, R. Epidemiology of neurodegeneration. Annu. Rev. Neurosci. 2003, 26: 81-104.

[2] Qiu, C., De Ronchi, D., Fratiglioni, L. The epidemiology of the dementias: an update. Curr. Opin. Psychiatry 2007, 20: 380-385.

[3] De Strooper, B., Annaert, W. Proteolytic processing and cell biological functions of the amyloid precursor protein. J. Cell Sci. 2000, 113 (Pt 11): 1857-1870.

[4] Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M.A., Biere, A.L., Curran, E., Burgess, T., Louis, J.C., Collins, F., Treanor, J., Rogers, G., Citron, M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286: 735-741.

[5] Sinha, S., Anderson, J.P., Barbour, R., Basi, G.S., Caccavello, R., Davis, D., Doan, M., Dovey, H.F., Frigon, N., Hong, J., Jacobson-Croak, K., Jewett, N., Keim, P., Knops, J., Lieberburg, I., Power, M., Tan, H., Tatsuno, G., Tung, J., Schenk, D., Seubert, P., Suomensaari, S.M., Wang, S., Walker, D., John, V., et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999, 402: 537-540.

[6] Buxbaum, J.D., Liu, K.N., Luo, Y., Slack, J.L., Stocking, K.L., Peschon, J.J., Johnson, R.S., Castner, B.J., Cerretti, D.P., Black, R.A. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 1998, 273: 27765-27767.

[7] Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C., Fahrenholz, F. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proceedings of the National Academy of Sciences of the United States of America 1999, 96: 3922-3927.

[8] Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., and Iwatsubo, T. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003, 422: 438-441.

[9] Kopan, R., and Ilagan, M.X. Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 2004, 5, 499-504.


Giuseppina Tesco M.D., Ph.D.
Genetics and Aging Research Unit
Mass General Institute for Neurodegenerative Disease (MIND)
Massachusetts General Hospital
114, 16th Street, Room 3900
Charlestown, MA 02129
USA
Tel: 617 724 9850
Fax: 617 724 1823
E-mail: tescog@helix.mgh.harvard.edu


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Advances on the Understanding of the Origins of Synaptic Pathology in AD
P.N. Lacor

Although Alzheimer’s disease (AD) was first discovered a century ago, we are still facing a lack of definitive diagnosis during the patient’s lifetime and are unable to prescribe a curative treatment. However, the past 10 years have seen a “revamping” of the main hypothesis about AD pathogenesis and the hope to foresee possible treatment. AD is no longer considered an irreversible disease. A major refinement of the classic β-amyloid cascade describing amyloid fibrils as neurotoxins has been made to integrate the key scientific evidences demonstrating that the first pathological event occurring in AD early stages affects synaptic function and maintenance. A concept fully compatible with synapse loss being the best pathological correlate of AD rather than other described neuropathological hallmarks (amyloid plaques, neurofibrillary tangles or neuronal death). The notion that synaptic alterations might be reverted, thus offering a potential curability, was confirmed by immunotherapy experiments targeting β-amyloid protein in transgenic AD mice in which cognitive functions were improved despite no reduction in the amyloid plaques burden. The updated amyloid cascade now integrates the synapse failure triggered by soluble Aβ-oligomers. Still no consensus has been reached on the most toxic Aβ conformations, neither on their site of production nor on their extra- versus intra-cellular actions. Evidence shows that soluble Aβ oligomers or ADDLs bind selectively to neurons at their synaptic loci, and trigger major changes in synapse composition and morphology, which ultimately leads to dendritic spine loss. However, the exact mechanism is not yet fully understood but is suspected to involve some membrane receptor(s).


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The Basic Biology of BACE1: A Key Therapeutic Target for Alzheimer’s Disease
S.L. Cole and R. Vassar

Alzheimer’s disease (AD) is an intractable, neurodegenerative disease that appears to be brought about by both genetic and non-genetic factors. The neuropathology associated with AD is complex, although amyloid plaques composed of the β-amyloid peptide (Aβ) are hallmark neuropathological lesions of AD brain. Indeed, Aβ plays an early and central role in this disease. β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the initiating enzyme in Aβ genesis and BACE1 levels are elevated under a variety of conditions. Given the strong correlation between Aβ and AD, and the elevation of BACE1 in this disease, this enzyme is a prime drug target for inhibiting Aβ production in AD. However, nine years on from the initial identification of BACE1, and despite intense research, a number of key questions regarding BACE1 remain unanswered. Indeed, drug discovery and development for AD continues to be challenging. While current AD therapies temporarily slow cognitive decline, treatments that address the underlying pathologic mechanisms of AD are completely lacking. Here we review the basic biology of BACE1. We pay special attention to recent research that has provided some answers to questions such as those involving the identification of novel BACE1 substrates, the potential causes of BACE1 elevation and the putative function of BACE1 in health and disease. Our increasing understanding of BACE1 biology should aid the development of compounds that interfere with BACE1 expression and activity and may lead to the generation of novel therapeutics for AD.


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Structural and Functional Determinants of γ-Secretase, an Intramembrane Protease Implicated in Alzheimer’s Disease
P.C. Fraering

Alzheimer’s disease is the most common form of neurodegenerative diseases in humans, characterized by the progressive accumulation and aggregation of amyloid-β peptides (Aβ) in brain regions subserving memory and cognition. These 39-43 amino acids long peptides are generated by the sequential proteolytic cleavages of the amyloid-β precursor protein (APP) by β- and γ-secretases, with the latter being the founding member of a new class of intramembrane-cleaving proteases (I-CliPs) characterized by their intramembranous catalytic residues hydrolyzing the peptide bonds within the transmembrane regions of their respective substrates. These proteases include the S2P family of metalloproteases, the Rhomboid family of serine proteases, and two aspartyl proteases: the signal peptide peptidase (SPP) and γ-secretase. In sharp contrast to Rhomboid and SPP that function as a single component, γ-secretase is a multi-component protease with complex assembly, maturation and activation processes. Recently, two low-resolution three-dimensional structures of γ-secretase and three high-resolution structures of the GlpG rhomboid protease have been obtained almost simultaneously by different laboratories. Although these proteases are unrelated by sequence or evolution, they seem to share common functional and structural mechanisms explaining how they catalyze intramembrane proteolysis. Indeed, a water-containing chamber in the catalytic cores of both γ-secretase and GlpG rhomboid provides the hydrophilic environment required for proteolysis and a lateral gating mechanism controls substrate access to the active site. The studies that have identified and characterized the structural determinants critical for the assembly and activity of the γ-secretase complex are reviewed here.


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Current Therapeutic Options for Alzheimer’s Disease
A. Lleó

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the developed world. The increasing life expectancy in the last years has led to an increase in the prevalence of this age-related condition and has posed an important medical and social challenge for developed societies. The mainstays of current therapy for AD rely on the cholinergic hypothesis developed more than 20 years ago. These compounds, known as acetylcholinesterase inhibitors (AChEIs), inhibit the cholinesterases and aim at improving the brain synaptic availability of acetylcholine. These drugs have been approved for the treatment of AD based on pivotal clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. Memantine, an NMDA antagonist, has been recently included as a therapeutic option for AD. Memantine can be combined safely with AChEIs for an additional symptomatic benefit. During the last years our understanding of the mechanisms underlying the pathogenesis of AD has markedly expanded. Several putative neuro-protective drugs are thoroughly investigated and many of them have reached the clinical arena. It can be anticipated that some of these drugs will be able to slow/prevent the progression of this condition in the near future.