Epilepsy and Cognitive Impairments in Alzheimer Disease

Palop, Jorge J.; Mucke, Lennart

doi:10.1001/archneurol.2009.15

Cited by 591 publications

(482 citation statements)

References 46 publications

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“…Higher levels of tau may also be responsible for the increased AD risk associated with a more common single nucleotide polymorphism in MAPT 58. Increased tau levels also predict the development of epilepsy, which is more frequent in patients with mild cognitive impairment (MCI) or AD than in control populations and may be associated with an earlier cognitive decline in AD 45, 48, 59.…”

Section: Discussionmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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A152T‐variant human tau (hTau‐A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau‐A152T or wild‐type hTau (hTau‐WT), we find age‐dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau‐A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau‐A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau‐A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co‐expression of hTau‐A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau‐A152T and amyloid‐β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.

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Section: Discussionmentioning

confidence: 99%

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

et al. 2016

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“…conditions in which hippocampal pathology has been shown to play a role, such as in AD (Palop and Mucke, 2009), and C9orf72-related motor neuron disease and frontotemporal lobe dementia (Al-Sarraj et al, 2011;Cooper-Knock et al, 2012), as well as possibly chronic traumatic encephalopathy (CTE) (McKee et al, 2013).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models, Neuropharmacology (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain-barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.

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“…Les oscillations  des souris importante dans la population atteinte par la forme sporadique de la maladie d'Alzheimer que chez les individus du même âge non atteints par la pathologie. Elle est même très anormalement élevée dans les cas familiaux précoces [7]. De ce fait, les activités cérébrales anormales, qui entraînent et/ou sont entraînées par l'accumulation des peptides A, représenteraient un événe-ment précoce au cours de la pathologie d'Alzheimer et contribueraient aux défi-cits cognitifs observés.…”

Section: Nouvelleunclassified

Comment les interneurones perdent la cadence dans le cerveau des souris modèles d’Alzheimer

Verret

2012

Med Sci (Paris)

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Epilepsy and Cognitive Impairments in Alzheimer Disease

Cited by 591 publications

References 46 publications

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Comment les interneurones perdent la cadence dans le cerveau des souris modèles d’Alzheimer

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