Acute Oral Bryostatin-1 Administration Improves Learning Deficits in the APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease

Schrott, Lisa M.; Jackson, Kasey L.; Yi, Pan; Dietz, Frank; Johnson, Gary S.; Basting, T.F.; Purdum, Geoffrey; Tyler, Theodore A.; Ríos, José D.; Castor, Trevor; Alexander, J. Steven

doi:10.2174/1567205012666141218141904

Cited by 45 publications

(35 citation statements)

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“…Perhaps repurposing PKC inhibitors for Alzheimer’s disease may prevent the effects of Aβ on synapses and thereby mitigate loss of cognitive function. In this regard, bryostatin 1, which causes the loss of PKC and failed in cancer therapies (Nezhat et al 2004), is in phase II clinical trials for Alzheimer’s disease (Nelson et al 2017), with mouse studies showing promising results in improving learning deficits in an Alzheimer’s disease mouse model (Russo et al 2015; Schrott et al 2015). It is noteworthy that targeting PKC in degenerative diseases may be particularly feasible as its activity would only need to be brought down from supraphysiological to physiological levels, essentially adjusting the balance to regain homeostasis.…”

Section: Pkc In Degenerative Disease: Gof Mutationsmentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

238

216

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Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are ‘receptors’ for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: protein kinase C isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer’s disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: “to go beyond is as wrong as to fall short.”

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Section: Pkc In Degenerative Disease: Gof Mutationsmentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

238

216

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“…However, crossing PS1 M146L with Tg2576 mice (or other APP mutants) caused an increase of amyloid production and deposition [28]. In particular, mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have been extensively used to better understand the pathogenic mechanisms underlying synaptic dysfunction and memory loss in AD, and to validate new therapeutic approaches [35–46]. These mice presented a robust age-dependent Aβ deposition in plaques preceded by an increase of soluble Aβ40 and Aβ42.…”

Section: Transgenic Models For the Study Of Admentioning

confidence: 99%

Rodent models for Alzheimer’s disease drug discovery

Puzzo

Gulisano

Palmeri

et al. 2015

Expert Opinion on Drug Discovery

182

113

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Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histophatological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals. Area covered This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including: APP Tg2576, APP/PS1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging. Expert opinion Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies.

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“…In some of the studies described above, the PKC isoform mediating the positive effects was shown to be either PKCa or PKCe [90,125,[127][128][129][130], supporting the idea that it may be beneficial to focus on developing specific activators for these isozymes. However, in several studiesespecially in in vivo studiesthe PKC isoforms responsible for the effects have not been identified [42,114,[117][118][119][120][121]126]. As PKC activation plays a role in several distinct pathological features of AD, targeting only a single PKC isoform may not be as effective as non-specific PKC activation (e.g.…”

Section: Pkc Activators As Potential Drug Candidates For Admentioning

confidence: 99%

Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision‐like Proteins?

Talman

Pascale

Jäntti

et al. 2016

Basic Clin Pharma Tox

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Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterized by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the embryonic lethal abnormal vision (ELAV)-like RNA-binding proteins that modulate the stability and the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD. Alzheimer's DiseaseAlzheimer's disease (AD) is a progressive neurodegenerative disorder, which leads to severe impairment of memory and cognitive functions, alterations in behaviour, incapacity for independent living and, finally, to death. It is the most common cause of dementia [1], which affects more than 35 million people worldwide [2]. The prevalence of both AD and dementia escalates along with increasing age. As the life span in developing countries rises, the number of people with dementia is expected to almost double every 20 years and reach 115 million in 2050 [2]. In the World Alzheimer Report 2013, it was estimated that in 2013, the global costs of dementia exceed US$600 billion, which is approximately 1% of global gross domestic product [3].The current pharmacological therapy for AD includes cholinesterase inhibitors (donepezil, rivastigmine and galantamine) as well as memantine, which is a low-affinity voltage-dependent uncompetitive antagonist of glutamatergic N-methyl-Daspartate (NMDA) receptors. Additionally, the neuropsychiatric symptoms are commonly treated with antidepressants and/or risperidone or other atypical antipsychotics. All of the available treatments are symptomatic and cannot cure or significantly inhibit the progression of the disease. Therefore, new disease-modifying treatments are urgently needed.The main neuropathological change characteristic to AD is the loss of cholinergic neurons in the nucleus basalis magnocellularis and their synapses, particularly in cerebral cortex, hippocampus and other subcortical structures that contribute to memory formation [4,5]. The underlying neuropathogenesis is not known, but the loss of neurons results from the accumulation of two distinctive pathological features: predominantly extracellular b amyloid (Ab) deposits (plaques) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau p...

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Acute Oral Bryostatin-1 Administration Improves Learning Deficits in the APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease

Cited by 45 publications

References 0 publications

Protein kinase C: perfectly balanced

Protein kinase C: perfectly balanced

Rodent models for Alzheimer’s disease drug discovery

Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision‐like Proteins?

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