Chapter 8 The Molecular and Cellular Pathogenesis of Dementia of the Alzheimer's Type

Luque, Francisco A.; Jaffe, Stephen L.

doi:10.1016/s0074-7742(09)00408-5

Cited by 21 publications

(11 citation statements)

References 55 publications

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“…Biomarkers of cardiovascular risk may be useful for identifying individuals at risk of future cognitive impairment, because oxidative stress and inflammation are implicated in the pathophysiology of dementia. Higher levels of oxidative stress, impaired cellular function linked to abnormal protein accumulation, and modification of molecular structures may have direct effects on neuronal structure and integrity, affecting cognitive function . Furthermore, inflammation is thought to be important in neurodegeneration, contributing to the development of some of the classic hallmarks of Alzheimer's pathology such as amyloid‐beta plaques .…”

Section: Discussionmentioning

confidence: 99%

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi‐Inflammatory Biomarkers

Harrison

Craen

Kerse

et al. 2016

J American Geriatrics Society

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Section: Discussionmentioning

confidence: 99%

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi‐Inflammatory Biomarkers

Harrison

Craen

Kerse

et al. 2016

J American Geriatrics Society

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“…Although abnormal processing of APP is one aspect of AD pathogenesis, hyperphosphorylation of cytosketal proteins, such as tau and neurofilaments, has also been well established as contributing to the AD phenotype (32, 34, 41). AD is a collective result of chronic and long‐term accumulation of stress or insults, such as oxidative stress (4, 6, 44), excitotoxic stress (45), inflammation, and abnormal cholesterol metabolism (46, 47), leading to synaptic dysfunction, cell death, and dementia. Amyloidogenic APP processing resulting in Aβ accumulation is known to cause toxicity in neuronal cells in vitro (48), which induces hyperphosphorylation of tau (18, 49).…”

Section: Discussionmentioning

confidence: 99%

A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice

Zheng²,

et al. 2012

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Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70-80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD.

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“…Among the latter are oxidative stress (56), inflammation, hormonal deficits, abnormal cholesterol metabolism (57,58), and exocitotoxic stress (59). Such defects result in synaptic function deficits, neuronal death, and dementia.…”

Section: Discussionmentioning

confidence: 99%

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

Zheng

Amin

et al. 2010

Journal of Biological Chemistry

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The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N-terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by A␤ peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or A␤ induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys 245 -Ala 277 . p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin-dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced A␤(1-42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases.The activity of Cdk5, a multifunctional serine/threonine kinase, is critical for neuronal development and synaptic activity; it sustains neurite outgrowth, neuronal migration, cortical lamination, and survival (1-9). Its activity depends on the binding of its neuron-specific, cyclin-related activators, p35 and p39 (10, 11). Cdk5 has also been implicated as a key player in learning and memory (12-15).Normally, Cdk5 activity is tightly regulated, but under conditions of neuronal stress, it is deregulated, leading to hyperactivity, neuronal pathology, and cell death. Accordingly, Cdk5 has been implicated in certain neurodegenerative disorders, such as AD.2 A model of the role of Cdk5 in neurodegeneration suggests that a stress-induced influx of calcium ions into neurons activates calpain, a Ca 2ϩ -activated protease, which cleaves p35 into p25 and a p10 fragment. p25, in turn, forms a more stable Cdk5-p25 hyperactive complex, which hyperphosphorylates Tau and induces cell death (16 -21). Indeed, increased levels of p25 and Cdk5 activity have been reported in AD brains. The finding that p25 may be toxic comes from studies of cortical neurons treated with ␤-amyloid (A␤), a key marker of AD pathology, where p35 is converted to p25 accompanied by activated Cdk5, Tau hyperphosphorylation, and apoptosis (22,23).Expression of the Cdk5-p25 complex seems to be primarily responsible for the Tau pathology ...

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Chapter 8 The Molecular and Cellular Pathogenesis of Dementia of the Alzheimer's Type

Cited by 21 publications

References 55 publications

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi‐Inflammatory Biomarkers

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi‐Inflammatory Biomarkers

A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

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