The structure and function of Alzheimer’s gamma secretase enzyme complex

Krishnaswamy, Sudarsan; Verdile, Giuseppe; Groth, David; Kanyenda, Limbikani J.; Martins, Ralph N.

doi:10.3109/10408360903335821

Cited by 59 publications

(41 citation statements)

References 210 publications

(202 reference statements)

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“…Despite a number of reports suggesting that PSEN mutations also affect Ca 2+ signaling by disturbing the Ca 2+ pool in the ER (Bezprozvanny & Mattson 2008), the origin of this disturbance is highly debated, contradictory and the literature remains confusing. What is true is that more is known about the function of presenilin substrates and their intracellular cleavage domains (ICDs) than presenilin itself (reviewed in Krishnaswamy et al 2009). Of particular importance regarding this chapter, the function of PSEN-dependent gamma-secretase in more distantly related and unicellular species has not been demonstrated or explored to any comparable extent.…”

Section: The Role Of Presenilins In Higher Organismsmentioning

confidence: 99%

Dictyostelium discoideum: Novel Insights into the Cellular Biology of Neurological Disorders

Myre¹

2012

Neurodegeneration

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Section: The Role Of Presenilins In Higher Organismsmentioning

confidence: 99%

Dictyostelium discoideum: Novel Insights into the Cellular Biology of Neurological Disorders

Myre¹

2012

Neurodegeneration

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“…A number of interacting proteins that are not components of c-SC also appear to play pivotal roles in modulating enzyme activity (Krishnaswamy et al, 2009). Recently, a novel c-SC inhibitor-based chemical probes which carries photoaffinity and biotin moieties for cross linking and purification respectively (Morohashi et al, 2006;Fuwa et al, 2007), was developed to directly identify the molecular target of the small compounds.…”

Section: C-secretase Inhibitorsmentioning

confidence: 99%

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

Shao

Zhou

Rudd

et al. 2011

The Anatomical Record

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One of the main neuropathological lesions observed in brain autopsy of Alzheimer's disease (AD) patients is the extracellular senile plaques mainly composed of amyloid-beta (Ab) peptide. Recently, treatment strategies have focused on modifying the formation, clearance, and accumulation of this potentially neurotoxic peptide. b-and c-secretase are responsible for the cleavage of amyloid precursor protein (APP) and the generation of Ab peptide. Treatments targeting these two critical secretases may therefore reduce Ab peptide levels and positive impact on AD. Vaccination is also an advanced approach against Ab. This review focuses on recent advances of our understanding of this key peptide, with emphasis on Ab peptide synthesis, accumulation and neurotoxicity, and current therapies including vaccination and two critical secretase inhibitors. MicroRNAs (miRNAs) are a class of conserved endogenous small noncoding RNAs, known to regulate the expression of complementary messenger RNAs, involved in AD development. We therefore address the relationship of miRNAs in the brain and Ab generation, as a novel therapeutic approach to the treatment of AD while also providing new insights on the etiology of this neurological disorder. Anat Rec, 294:1307Rec, 294: -1318Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

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“…To inhibit abnormal processing of AβPP and accumulation of toxic AβPP-Aβ, gamma secretases have been targeted (205,206). Although this approach seems promising for lowering plasma, CSF, and brain AβPP-Aβ burden (203,207), the objective clinical therapeutic responses have been minimal or undetectable (205,208,209). Worse yet, these drugs are highly toxic due to concurrent inhibition of Notch signaling (203,206), which mediates neuronal plasticity, cognition, and long-term memory (210).…”

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confidence: 99%

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

Monte

2012

Front Biosci

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Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential. KeywordsAmyloid; Anti-oxidants; Brain diabetes; Brain insulin resistance; Incretins; Insulin; Insulin sensitizers; Liver-Brain-Axis; Metal Chelation; Neuroprotection; Nitrosamine; Oxidative Stress; Polyphenols; Statins; Streptozotocin; Tau; Type 3 diabetes INTRODUCTIONThe gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and amyloid-beta 40-42 kD fragments of amyloid beta precursor protein (AβPP-Aβ) deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of Send correspondence to: Suzanne M. de la Monte, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI. 02903, Tel: 401-444-7364, Fax: 401-444-2939, Suzanne_DeLaMonte_MD@Brown.edu. HHS Public Access Author manuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 2015 August 26. Published in final edited form as:Front Biosci (Elite Ed). ; 4: 1582-1605. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity (1).To improve diagnosis and treatment, we must learn to connect the development and progression of neurodegeneration with molecular, biochemical, physiological, neuroimaging, and clinical abnormalities in AD. Several strategies could be taken to advance this proc...

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The structure and function of Alzheimer’s gamma secretase enzyme complex

Cited by 59 publications

References 210 publications

Dictyostelium discoideum: Novel Insights into the Cellular Biology of Neurological Disorders

Dictyostelium discoideum: Novel Insights into the Cellular Biology of Neurological Disorders

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

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