Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Denvir, James; Neitch, Shirley M.; Fan, Jun; Niles, Richard M.; Boskovic, Goran; Schreurs, Bernard G.; Primerano, Donald A.; Alkon, Daniel L.

doi:10.3233/jad-150051

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…Therefore, based on its high affinity for PKC and lack of tumour-promoting properties, bryostatin-1 can be considered as the most promising drug candidate among PKC activators so far. It is currently under investigation for the treatment of AD in clinical trials (www.clinicaltrials.gov), and a recent paper reported its use in one early-onset AD patient with limb spasticity and loss of speech [138]. According to this study, treatment with bryostatin-1 leads to improvement in limb motion, attentional focus and vocalization.…”

Section: Pkc Activators As Potential Drug Candidates For Admentioning

confidence: 93%

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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Section: Pkc Activators As Potential Drug Candidates For Admentioning

confidence: 93%

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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“…Abbreviations: PPA, logopenic variant primary progressive aphasia; nfvPPA, nonfluent variant PPA; svPPA, semantic variant PPA. Table 1 Pathogenic variants identified within the main AD and FTD genes [27] p.Gly35GlufsTer19 1 familial [28] IVS3 -2delA 1 familial [29] p.Gln130SerfsTer124 1 familial [27] p.Cys139Arg 1 sporadic [30] p.Cys157LysfsTer97 1 familial and 1 sporadic [31][32][33] p.Arg161GlyfsTer36 1 sporadic [34] IVS7+ 1delTGAG 1 familial [35] IVS7-1G > A 5 familial [36] p.Gln257ProfsTer27 1 familial [37] p.Thr272SerfsTer10 6 familial and 1 sporadic [38,39] p.Gln300Ter 1 familial [37] p.Cys366fsTer1 1 familial [30] p.Gln415Ter 1 sporadic [27] p.Val452TrpfsTer38 1 familial [27] p.Arg493Ter 1 familial [27] p.Cys521Tyr 1 familial [40] MAPT p.Gly639Ser 1 familial [41] p.Val698Ile 1 familial [42] p.Gly724Arg 1 sporadic [43] C9orf72 repeat expansion 3 familial [30,44] 1 sporadic PSEN1 p.Thr147Ile 1 familial [45] p.Pro264Leu 1 familial [46] svPPA GRN p.Thr409Met 1 familial [47] MAPT p.Pro636Leu 1 familial [48] IVS10+ 16C>T 13 familial [27] C9orf72 Repeat expansion 1 familial and 2 sporadic [44,[49][50][51] 3 not specified TREM2 p.Gln33Ter 2 sporadic [52] lvPPA GRN p.M1? 1 familial [53] Not specified 5 familial [49,…”

Section: Supplementary Materialsmentioning

confidence: 99%

Genetic screen in a large series of patients with primary progressive aphasia

Ramos

Dokuru

Berlo

et al. 2018

Alzheimer's & Dementia

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Introduction-Primary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease. Methods-We screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases. Results-In this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP. Rare risk variants, TREM2 R47H and MAPTA152T, were associated with a three-to seven-fold increase in risk for PPA. Discussion-Our results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43-than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.

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“…EA subject #2 was given 11 infusions over 6 months as described previously [ 43 ] (identified as IV-18). The patient showed increased vocalization of words, responses to verbal commands, increased swallowing (after many months of requiring tube-feeding), primitive conversational interaction, and some increased range of limb motion.…”

Section: Resultsmentioning

confidence: 99%

Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer’s Disease Phase IIa and Expanded Access Trials

Nelson

Sun

Lim

et al. 2017

JAD

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Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer’s disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus –1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

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Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Cited by 10 publications

References 33 publications

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

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

Genetic screen in a large series of patients with primary progressive aphasia

Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer’s Disease Phase IIa and Expanded Access Trials

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