REVIEW: γ‐Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current State

Panza, Francesco; Frisardi, Vincenza; Imbimbo, Bruno P.; Capurso, Cristiano; Logroscino, Giancarlo; Sancarlo, Daniele; Seripa, Davide; Vendemiale, Gianluigi; Pilotto, Alberto; Solfrizzi, Vincenzo

doi:10.1111/j.1755-5949.2010.00164.x

Cited by 64 publications

(46 citation statements)

References 79 publications

(115 reference statements)

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“…In recent years, important physiological functions have been identified for spontaneous excitatory neurotransmission (McKinney et al, 1999;Sharma and Vijayaraghavan, 2003;Sutton et al, 2006;Espinosa and Kavalali, 2009). The current study thus adds to the growing list of potential deleterious consequences of using ␥-secretase inhibitors to treat AD (Panza et al, 2010).…”

Section: Discussionmentioning

confidence: 82%

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Pratt¹,

Zhu²,

Watari³

et al. 2011

J. Neurosci.

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With a multitude of substrates, ␥-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of ␥-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of ␥-secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support ␥-secretase activity. Treatment of WT neuronal cultures with ␥-secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for ␥-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals.

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Section: Discussionmentioning

confidence: 82%

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Pratt¹,

Zhu²,

Watari³

et al. 2011

J. Neurosci.

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“…Mouse models tend to confi rm the idea that overproduction of A b can lead to neurotoxicity, but the degree of neurotoxicity seems modest when judged by the standard of human disease: massive amyloid accumulation in mice leads to a demonstrable but only moderate memory loss, and rather modest histological evidence of neurodegeneration, e.g., one study of a transgenic mouse model using the Swedish b -APP model (Irizarry et al 1997 ) . In contrast, conditional Panza et al ( 2010 ) knockout of presenilins in the adult cerebral cortex lead to severe and progressive neurodegeneration, with some features (e.g., tau hyperphosphorylation) similar to that observed in human AD (Saura et al 2004). Although this model provides clear evidence of memory loss, impairment of synaptic plasticity, and neurodegeneration, many different experimental manipulations could injure neurons, and thus, it remains unclear how completely this model replicates human disease.…”

Section: G -Secretase Inhibitorsmentioning

confidence: 88%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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“…1) argues that the accumulation of the β-amyloid (Aβ) peptide leading to its aggregation and formation of senile plaques (SP)s which triggers pathophysiological changes of the brain and ultimately leads to cognitive dysfunction. The development of the senile plaque is thought to precede and precipitate the formation of neurofibrilliary tangles and oligomeric forms of Aβ which are reported to be the main cause of neuronal death [8,9]. Aβ is produced by a series of enzymes known as secretases [7].…”

Section: Amyloid Hypothesismentioning

confidence: 99%

Enzyme Inhibitors Involved in the Treatment of Alzheimer’s Disease

Revadigar

Ghalib

Murugaiyah

et al. 2014

Drug Design and Discovery in Alzheimer's Disease

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REVIEW: γ‐Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current State

Cited by 64 publications

References 79 publications

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Enzyme Inhibitors Involved in the Treatment of Alzheimer’s Disease

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