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Alzheimer Disease: HELP
Articles by Haakon B. Nygaard
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Haakon B. Nygaard wrote the following 13 articles about Alzheimer Disease.
 
+ Citations + Abstracts
1 Review Targeting Fyn Kinase in Alzheimer's Disease. 2018

Nygaard, Haakon B. ·Division of Neurology, Department of Medicine, University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada. Electronic address: haakon.nygaard@ubc.ca. ·Biol Psychiatry · Pubmed #28709498.

ABSTRACT: The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.

2 Review Epileptic activity in Alzheimer's disease: causes and clinical relevance. 2017

Vossel, Keith A / Tartaglia, Maria C / Nygaard, Haakon B / Zeman, Adam Z / Miller, Bruce L. ·Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: kvossel@umn.edu. · Department of Neurology, University of Toronto, ON, Canada. · Division of Neurology, University of British Columbia, Vancouver, BC, Canada. · Cognitive Neurology Research Group, University of Exeter Medical School, Exeter, UK. · Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. ·Lancet Neurol · Pubmed #28327340.

ABSTRACT: Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer's disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer's disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer's disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer's disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer's disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

3 Review Current and emerging therapies for Alzheimer's disease. 2013

Nygaard, Haakon B. ·Department of Neurology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: haakon.nygaard@yale.edu. ·Clin Ther · Pubmed #24139420.

ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with a rapidly increasing worldwide prevalence. Although no cure for AD has yet been found, substantial progress has been made in our understanding of AD pathogenesis. This progress has led to the development of numerous promising compounds in various stages of clinical testing. In this review, the current pharmacologic treatments for AD are discussed in detail, followed by an overview of the main experimental strategies that will shape AD therapeutics over the next decade.

4 Article Delayed daily activity and reduced NREM slow-wave power in the APPswe/PS1dE9 mouse model of Alzheimer's disease. 2019

Kent, Brianne A / Michalik, Mateusz / Marchant, Elliott G / Yau, Kiana W / Feldman, Howard H / Mistlberger, Ralph E / Nygaard, Haakon B. ·Djavad Mowafaghian Centre for Brain Health, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada. · Department of Psychology, Simon Fraser University, Burnaby, Canada. · Department of Psychology, Vancouver Island University, Nanaimo, Canada. · Department of Neurosciences, University of California, San Diego, USA. · Department of Psychology, Simon Fraser University, Burnaby, Canada. Electronic address: mistlber@sfu.ca. · Djavad Mowafaghian Centre for Brain Health, Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada. Electronic address: haakon.nygaard@ubc.ca. ·Neurobiol Aging · Pubmed #30884411.

ABSTRACT: Alzheimer's disease (AD) is associated with disrupted circadian rhythms and sleep, which are thought to reflect an impairment of internal circadian timekeeping that contribute to clinical symptoms and disease progression. To evaluate these hypotheses, a suitable preclinical model of AD is needed. We performed a comprehensive assessment of circadian rhythms and sleep in the APP

5 Article Whole-Exome Sequencing of an Exceptional Longevity Cohort. 2019

Nygaard, Haakon B / Erson-Omay, E Zeynep / Wu, Xiujuan / Kent, Brianne A / Bernales, Cecily Q / Evans, Daniel M / Farrer, Matthew J / Vilariño-Güell, Carles / Strittmatter, Stephen M. ·Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut. · Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, British Columbia, Canada. · Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR), Yale University School of Medicine, New Haven, Connecticut. ·J Gerontol A Biol Sci Med Sci · Pubmed #29750252.

ABSTRACT: Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and super-cententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole-exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including LYST, MDN1, and RBMXL1. Several genes with variants conferring an increased risk for AD and other dementias were identified, including TREM2, EPHA1, ABCA7, PLD3, MAPT, and NOTCH3. Larger centenarian studies will be required to further elucidate the genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.

6 Article Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576. 2018

Kent, Brianne A / Strittmatter, Stephen M / Nygaard, Haakon B. ·Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada. · Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA. ·J Alzheimers Dis · Pubmed #29991134.

ABSTRACT: BACKGROUND: Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. OBJECTIVE: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD. METHODS: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. RESULTS: Both the APP/PS1 model at 8- 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. CONCLUSION: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.

7 Article Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models. 2015

Kostylev, Mikhail A / Kaufman, Adam C / Nygaard, Haakon B / Patel, Pujan / Haas, Laura T / Gunther, Erik C / Vortmeyer, Alexander / Strittmatter, Stephen M. ·From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and. · From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520. · the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06536 and. · From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520 stephen.strittmatter@yale.edu. ·J Biol Chem · Pubmed #26018073.

ABSTRACT: Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD.

8 Article Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. 2015

Kaufman, Adam C / Salazar, Santiago V / Haas, Laura T / Yang, Jinhee / Kostylev, Mikhail A / Jeng, Amanda T / Robinson, Sophie A / Gunther, Erik C / van Dyck, Christopher H / Nygaard, Haakon B / Strittmatter, Stephen M. ·Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT. · Department of Neurology, Yale University School of Medicine, New Haven, CT. · Department of Psychiatry, Yale University School of Medicine, New Haven, CT. ·Ann Neurol · Pubmed #25707991.

ABSTRACT: OBJECTIVE: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. METHODS: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. RESULTS: AZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. INTERPRETATION: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.

9 Article A Novel Presenilin 1 Mutation in Early-Onset Alzheimer's Disease With Prominent Frontal Features. 2014

Nygaard, Haakon B / Lippa, Carol F / Mehdi, Djekidel / Baehring, Joachim M. ·Department of Neurology, Yale University School of Medicine, New Haven, CT, USA haakon.nygaard@yale.edu. · Department of Neurology, Drexel University, Philadelphia, PA, USA. · Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA. · Department of Neurology, Yale University School of Medicine, New Haven, CT, USA. ·Am J Alzheimers Dis Other Demen · Pubmed #24463146.

ABSTRACT: Familial Alzheimer's disease (AD) is a rare disorder involving known autosomal dominant mutations in the amyloid precursor protein and presenilin (PSEN) 1 and 2. Here, we present a case of early-onset AD with prominent frontal features associated with a novel deletion of codon 40 in the PSEN1 gene. Serial brain magnetic resonance imaging and(18)F florbetapir imaging show prominent involvement of the frontal lobes, corresponding with the clinical presentation. This case report illustrates a possible link between a novel PSEN1 mutation and frontal variant AD.

10 Article Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. 2013

Um, Ji Won / Kaufman, Adam C / Kostylev, Mikhail / Heiss, Jacqueline K / Stagi, Massimiliano / Takahashi, Hideyuki / Kerrisk, Meghan E / Vortmeyer, Alexander / Wisniewski, Thomas / Koleske, Anthony J / Gunther, Erik C / Nygaard, Haakon B / Strittmatter, Stephen M. ·Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT 06536, USA. ·Neuron · Pubmed #24012003.

ABSTRACT: Soluble amyloid-β oligomers (Aβo) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrP(C)). At the postsynaptic density (PSD), extracellular Aβo bound to lipid-anchored PrP(C) activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrP(C) with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrP(C)-bound Aβo to activate Fyn. PrP(C) and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrP(C) generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Aβo-PrP(C)-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Aβo-PrP(C) complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.

11 Article Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. 2012

Um, Ji Won / Nygaard, Haakon B / Heiss, Jacqueline K / Kostylev, Mikhail A / Stagi, Massimiliano / Vortmeyer, Alexander / Wisniewski, Thomas / Gunther, Erik C / Strittmatter, Stephen M. ·Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA. ·Nat Neurosci · Pubmed #22820466.

ABSTRACT: Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Aβ-PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Aβ engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.

12 Article Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model. 2010

Zhang, Yongfang / Kurup, Pradeep / Xu, Jian / Carty, Nikisha / Fernandez, Stephanie M / Nygaard, Haakon B / Pittenger, Christopher / Greengard, Paul / Strittmatter, Stephen M / Nairn, Angus C / Lombroso, Paul J. ·Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA. ·Proc Natl Acad Sci U S A · Pubmed #20956308.

ABSTRACT: Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder. Early in the pathophysiology of AD, synaptic function is disrupted by soluble Aβ oligomers, possibly through Aβ-mediated internalization of NMDA receptors. Striatal-enriched phosphatase (STEP) is a tyrosine phosphatase that regulates the internalization of NMDA receptors. Recent work shows that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Here, we use genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model and show that a decrease in STEP levels reverses cognitive and cellular deficits observed in these mice. Our results suggest that STEP inhibitors may prove therapeutic for this devastating disorder.

13 Article Memory impairment in transgenic Alzheimer mice requires cellular prion protein. 2010

Gimbel, David A / Nygaard, Haakon B / Coffey, Erin E / Gunther, Erik C / Laurén, Juha / Gimbel, Zachary A / Strittmatter, Stephen M. ·Cellular Neuroscience, Neurodegeneration, and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA. ·J Neurosci · Pubmed #20445063.

ABSTRACT: Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).