Neuropeptide Abnormalities in Patients With Early Alzheimer Disease

Davis, Kenneth L.; Mohs, Richard C.; Marin, Deborah B.; Purohit, Dushyant P.; Perl, Daniel P.; Lantz, Melinda; Austin, Gregory L.; Haroutunian, Vahram

doi:10.1001/archpsyc.56.11.981

Cited by 73 publications

(45 citation statements)

References 36 publications

(38 reference statements)

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“…This suggests that interactions between neurotransmitter systems are significant for the production of adaptive behavior (Decker and McGaugh, 1991). The findings also suggest a link between the cognitive and behavioral impairments that occur in Alzheimer disease and the fact that multiple neurotransmitter systems such as cholinergic, noradrenergic, and serotonergic systems are typically impaired in the brain of Alzheimer patients (Chen et al, 2000;Davis et al, 1999;Dringenberg, 2000;Francis et al, 1999;Lai et al, 2002;Reinikainen et al, 1990). Our previous studies confirmed that neither PRO nor pCPA given individually impaired WM performance, and that scopolamine impaired naive but not WM strategiespretrained rats (Beiko et al, 1997;Saber and Cain, 2003).…”

Section: Introductionmentioning

confidence: 51%

“…However, the current use of anticholinesterase drugs to improve cholinergic function has not been fully effective for many patients, and debate continues about their costeffectiveness (AD2000 Collaborative Group, 2004). This is probably because Alzheimer disease typically involves the vast loss of synaptic contacts in cortex and elsewhere that normally release a number of brain neurotransmitter and neuropeptide systems including cholinergic, serotonergic, b-adrenergic, somatostatinergic, and GABAergic systems (Chen et al, 2000;Davis et al, 1999;Francis et al, 1999;Reinikainen et al, 1990), and this loss of multiple, often interacting systems may be important for the severe cognitive and behavioral impairments in Alzheimer patients. If true, optimal pharmacological treatment will require agents directed at a number of different systems in combination.…”

Section: Implications For Alzheimer Diseasementioning

confidence: 99%

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Combined but not Individual Administration of β-Adrenergic and Serotonergic Antagonists Impairs Water Maze Acquisition in the Rat

Kenton

Boon

Cain

2007

Neuropsychopharmacol

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This study examined the effects of serotonergic depletion and b-adrenergic antagonism on performance in both visible platform and hidden platform versions of the water maze task. Male Long-Evans rats received systemic injections of p-chlorophenylalanine (500 mg/ kg Â 2) to deplete serotonin, or propranolol (20 or 40 mg/kg) to antagonize b-adrenergic receptors. Some rats received treatments in combination. To separate strategies learning from spatial learning, half of the rats underwent Morris' water maze strategies pretraining before drug administration and spatial training. Individual depletion of serotonin or antagonism of b-adrenergic receptors caused few or no impairments in either naive or pretrained rats in either version of the task. In contrast, combined depletion of serotonin and antagonism of b-adrenergic receptors impaired naive rats in the visible platform task and impaired both naive and strategies-pretrained rats in the hidden platform task, and also caused sensorimotor impairments. This is the first finding of a 'global' water maze task/ sensorimotor impairment with combined administration of two agents that, at the high doses that were given individually, produced few or no impairments. The data imply that (1) serotonergic and b-adrenergic systems may interact in a manner that is important for adaptive behavior; (2) impairments in these systems found in Alzheimer patients may be important for their cognitive and behavioral impairments; and (3) the approach used here can model aspects of the cognitive and behavioral impairments in Alzheimer disease.

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Section: Introductionmentioning

confidence: 51%

Section: Implications For Alzheimer Diseasementioning

confidence: 99%

Combined but not Individual Administration of β-Adrenergic and Serotonergic Antagonists Impairs Water Maze Acquisition in the Rat

Kenton

Boon

Cain

2007

Neuropsychopharmacol

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“…This early principal cell neurodegeneration in the entorhinal cortex was previous to that seen in hippocampus (18 months) as described in AD patients. Moreover, both brain areas in this transgenic mice display a prominent early reduction of SOM/NPY interneurons of GABA system [3,4] as occurs in AD brains [5][6][7][8][9][10][11][12]. Therefore, this PS1/AβPP mouse could mimic the initial stages of the pathology in humans and could be of great interest to analyze the age-dependent vulnerability of different neuronal subpopulations to this disease.…”

Section: Introductionmentioning

confidence: 87%

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

Baglietto‐Vargas

Moreno-González

Sánchez-Varo

et al. 2010

JAD

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Abstract. Specific neuronal networks are preferentially affected in the early stages of Alzheimer's disease (AD). The distinct subpopulations of hippocampal inhibitory GABAergic system have been shown to display differential vulnerability to neurodegeneration in AD. We have previously reported a substantial loss of SOM/NPY interneurons, whereas those expressing parvalbumin were unaltered, in the hippocampus of 6 month-old PS1/AβPP transgenic mice. In the present study, we now investigated the pathological changes of hippocampal calretinin (CR) interneurons in this PS1/AβPP model from 2 to 12 months of age. The total number of CR-immunoreactive inhibitory cells was determined by stereology in CA1 and CA2/3 subfields. Our findings show a substantial decrease (35%-45%) of CR-positive interneurons in both hippocampal subfields of PS1/AβPP mice at very early age (4 months) compared to age-matched control mice. This decrease was accompanied by a reduced CR mRNA content as determined by quantitative RT-PCR. However, the number of another hippocampal CR-positive population (belonging to Cajal-Retzius cells) was not affected. The selective early loss of CR-interneurons was parallel to the appearance of extracellular Aβ deposits, preferentially in CR-axonal fields, and the formation of dystrophic neurites. This specific GABAergic subpopulation plays a crucial role in the generation of synchronous rhythmic activity in hippocampus by controlling other interneurons. Therefore, early alterations of hippocampal inhibitory functionality in AD, caused by select CR-cells neurodegeneration, could result in cognitive impairments seen in initial stages of the disease.

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“…The CRF family of signaling molecules is broadly involved in physiological and behavioral responses to stress (Chadwick et al, 1993) and undergoes alterations early in AD progression (Davis et al, 1999). However, the nature of its involvement in AD neuropathology is unclear.…”

Section: Crfrs Differentially Regulate Stress-induced Tau Phosphorylamentioning

confidence: 99%

Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

Rissman¹,

Lee²,

Vale³

et al. 2007

Journal of Neuroscience

135

147

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Hyperphosphorylation of the microtubule-associated protein tau is a key event in the development of Alzheimer's disease (AD) neuropathology. Acute stress can induce hippocampal tau phosphorylation (tau-P) in rodents, but the mechanisms and pathogenic relevance of this response are unclear. Here, we find that hippocampal tau-P elicited by an acute emotional stressor, restraint, was not affected by preventing the stress-induced rise in glucocorticoids but was blocked by genetic or pharmacologic disruption of signaling through the type 1 corticotropin-releasing factor receptor (CRFR1). Conversely, these responses were exaggerated in CRFR2-deficient mice. Parallel CRFR dependence was seen in the stress-induced activation of specific tau kinases. Repeated stress exposure elicited cumulative effects on tau-P and its sequestration in an insoluble, and potentially pathogenic, form. These findings support differential regulatory roles for CRFRs in an AD-relevant form of neuronal plasticity and may link datasets documenting alterations in the CRF signaling system in AD and implicating chronic stress as a risk factor in age-related neurological disorders.

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Neuropeptide Abnormalities in Patients With Early Alzheimer Disease

Cited by 73 publications

References 36 publications

Combined but not Individual Administration of β-Adrenergic and Serotonergic Antagonists Impairs Water Maze Acquisition in the Rat

Combined but not Individual Administration of β-Adrenergic and Serotonergic Antagonists Impairs Water Maze Acquisition in the Rat

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

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