β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

Murray, Patrick S.; Kirkwood, Caitlin M.; Gray, Megan C.; Ikonomović, Miloš D.; Paljug, William R.; Abrahamson, Eric E.; Henteleff, Ruth; Hamilton, Ronald L.; Kofler, Julia; Klunk, William E.; López, Oscar L.; Penzes, Peter; Sweet, Robert A.

doi:10.1016/j.neurobiolaging.2012.02.015

Cited by 43 publications

(59 citation statements)

References 67 publications

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“…Interestingly, beyond impairment of memory and cognition, Alzheimer disease is also an attention disorder and as such shares behaviors reminiscent of attention deficit hyperactivity disorder and obsessive compulsive behavior (42). A subset of Alzheimer patients also exhibits psychosis (43,44). The current study advances a plausible hypothesis that aspects of these brain disorders are attributable to defective myelination and deficiency of ␥-secretase, a pivotal developmental regulator for multiple developmental pathways.…”

Section: Discussionmentioning

confidence: 68%

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Dries

Zhu²,

Brooks³

et al. 2016

Journal of Biological Chemistry

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The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of ␥-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate ␥-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessivecompulsive disorder is a distinct subtype of schizophrenia.Psychiatric diseases such as schizophrenia, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and autism exert devastating impact on the well-being of those affected and the society at large. The clinical symptoms and etiologies of these diseases are complex, obscure, and often overlap, and characteristics of these diseases can only be partially and incompletely captured in existing animal models. In contrast to classical neurological disorders such as Alzheimer disease, psychiatric disorders do not display overt neuropathological lesions but rather are attributed to changes in synaptic transmission, neuronal homeostasis, and neuronal networks. Both genetic and environmental factors contribute to these changes, which can result from multiple, individually rare genetic alterations or from large numbers of common genetic variants. Often, psychiatric disorders have their origins in perturbed neurodevelopment. It is therefore conceivable that key neurodevelopmental factors and pathways contribute to their neurobiological underpinnings.Several important neurodevelopmental pathways are controlled by ␥-secretase, a multisubunit, multitransmembranespanning proteolytic complex that cleaves a host of type I transmembrane proteins within the lipid bilayer (1). Although ␥-secretase is perhaps best known for its role in cleaving the amyloid precursor protein in Alzheimer disease, key ␥-secretase substrates have also been implicated in schizophrenia, most notably neuregulin-1 (Nrg1) and its receptor ErbB4 (2, 3). A recent study also demonstrated a functional interaction between the amyloid precursor protein and disrupted-in-schizophrenia-1 in cortical development (4). Moreover, multiple ...

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Section: Discussionmentioning

confidence: 68%

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Dries

Zhu²,

Brooks³

et al. 2016

Journal of Biological Chemistry

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“…Several neurobiological factors potentially contribute to psychosis in AD: genetic substrate (26), neurochemical alterations (27), neurofibrillary tangle density (28), and amyloid burden (29). The research findings vary considerably and study samples have generally been small.…”

Section: Discussionmentioning

confidence: 99%

Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease

Sultzer

Leskin

Melrose

et al. 2014

The American Journal of Geriatric Psychiatry

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Objectives Delusional thoughts are common among patients with Alzheimer’s disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information which fosters inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This study’s goals were to examine the clinical associations among delusions, memory deficits, and poor insight, explore neurobiological correlates for these symptoms, and identify shared mechanisms. Design Cross sectional analysis. Setting VA Greater Los Angeles Healthcare System. Participants Eighty-eight outpatients with AD (mean MMSE 19.3). Measurements Delusional thoughts were assessed with the Neuropsychiatric Inventory. Level of inaccurate insight was assessed with the Neurobehavioral Rating Scale (NRS). Memory was assessed with the Mattis Dementia Rating Scale (DRS) memory subscale. 18F-FDG PET imaging was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. Results Patients with delusions had lower DRS memory subscale scores. NRS inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight. Conclusions Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight.

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“…Individuals underwent neurologic, neuropsychological, psychiatric, and neuropathologic evaluations as part of the participation in the ADRC as previously described (17)(18)(19).…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein E4 (APOE4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

Sweet

MacDonald²,

Kirkwood³

et al. 2016

Molecular & Cellular Proteomics

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It has been hypothesized that Alzheimer disease (AD) is primarily a disorder of the synapse. However, assessment of the synaptic proteome in AD subjects has been limited to a small number of proteins and often included subjects with end-stage pathology. Protein from prefrontal cortex gray matter of 59 AD subjects with mild to moderate dementia and 12 normal elderly subjects was assayed using targeted mass spectrometry to quantify 191 synaptically expressed proteins. The profile of synaptic protein expression clustered AD subjects into two groups. One of these was characterized by reduced expression of glutamate receptor proteins, significantly increased synaptic protein network coexpression, and associated with Apolipoprotein E*4 (APOE*4) carrier status. The second group, by contrast, showed few differences from control subjects.

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β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

Cited by 43 publications

References 67 publications

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease

Apolipoprotein E4 (APOE4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

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β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

Cited by 43 publications

References 67 publications

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease

Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

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Apolipoprotein E4 (APOE4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease