GABAergic Deafferentation Hypothesis of Brain Aging and Alzheimer’s Disease Revisited

Marczynski, T.J.

doi:10.1016/s0361-9230(97)00347-x

Cited by 87 publications

(49 citation statements)

References 267 publications

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“…Postmenopausal women taking estrogen replacement therapy are at lower risk of developing Alzheimer’s disease [30], and postmortem brains of patients with Alzheimer’s disease also show a marked increase in GABA synthesis [31]. However, many conventional replacement therapies contain progesterone compounds.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Prevents Estradiol-Induced Dendritic Spine Formation in Cultured Hippocampal Neurons

Murphy

Segal

2000

Neuroendocrinology

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Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brain-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protein (CREB) in response to enhanced activity levels. Interestingly, progesterone was shown to counteract the effects of estradiol on dendritic spine density in vivo and in vitro. The present study examined how progesterone may act to block the effects of estradiol in the molecular cascade of cellular events leading to formation of dendritic spines. Progesterone did not affect the estradiol-induced downregulation of BDNF or GAD, but it did block the effect of estradiol on CREB phosphorylation. The latter effects of progesterone on the pCREB response and spine formation were reversed by indomethacin, which prevents the conversion of progesterone to the neurosteroid tetrahydroprogesterone (THP). We therefore examined if the progesterone effects were caused by its active metabolite THP. Progesterone treatment caused a 60-fold increase in THP in the culture medium. THP itself enhanced spontaneous GABAergic activity in patch-clamped cultured neurons. Finally, THP blocked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradiol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultured network.

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Section: Discussionmentioning

confidence: 99%

Progesterone Prevents Estradiol-Induced Dendritic Spine Formation in Cultured Hippocampal Neurons

Murphy

Segal

2000

Neuroendocrinology

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“…An involvement of the gamma-aminobutyric acid (GABA)ergic system in Alzheimer-related neuropathological changes has been demonstrated (1,2). In particular, different benzodiazepine receptor agonists or antagonists are able to influence cognitive function by modulating GABAergic function in the brain (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer's disease and vascular dementia

Bernardi

Lanzone

Cento

et al. 2000

European Journal of Endocrinology

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Objective: Neurosteroids have been suggested to be involved in the regulation of cognitive performances. A major neurosteroid gamma-aminobutyric acid (GABA) agonist is allopregnanolone: the main source of circulating allopregnanolone is the adrenal cortex. Studies indicated that a disturbance of the central regulation of the hypothalamic-pituitary-adrenocortical axis occurs in both senile (Alzheimer's disease: AD) and vascular dementia (VD). Design: The aim of the present study was to evaluate the levels of circulating allopregnanolone, dehydroepiandrosterone (DHEA) and cortisol and their response to corticotropin-releasing factor (CRF) test in AD and VD. Methods: Three groups of 12 subjects were included in the study: AD, VD and age-matched control subjects. CRF test was performed in all subjects and allopregnanolone, DHEA and cortisol levels were measured every 15 min for 2 h. Results: Mean Ϯ S.E.M. allopregnanolone and DHEA basal levels were significantly lower in AD and VD than in controls, while cortisol levels were significantly higher than in controls (P<0.01). Allopregnanolone and DHEA levels increase in response to CRF test in all subjects but the area under curve (AUC) in patients was significantly lower than in controls (P<0.01). Cortisol secretion appeared to be very sensitive in response to CRF stimulation: in fact, cortisol response to CRF test in AD and VD subjects was higher (both as AUC and as % max increase) than in controls (P<0.01). Conclusions:The present study firstly showed that allopregnanolone levels are reduced both in AD and in VD and that dementia has a preserved stimulated response of allopregnanolone to CRF. Overall, however, the total response of allopregnanolone to CRF remains reduced in respect to controls. Further studies are necessary for a better understanding of the role of neurosteroids in the regulation of cognitive function.

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“…The adenosine triphosphate (ATP)-mediated control of GABA synthesis gradually declines with age and AD-related neurodegeneration (Marczynski, 1998). Additionally, GAD has been associated with short-term plasticity (Ramsey et al, 2004), and the neurological deficits resulting from brain injury-induced white matter lesions (Robinson et al, 2006).…”

Section: Gadmentioning

confidence: 99%

Vietnam Head Injury Study - Phase III: A 30-Year Post-Injury Follow-Up Study

Grafman¹

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 01-08-20072. REPORT TYPE (From -To) Final DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERThe Henry M. Jackson Foundation Rockville, MD 20852 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe Vietnam Head Injury Study -Phase III (VHIS-P3) experienced contractual and logistical delays early on in the project, but by April 2004 all contracts, space allocation, and IRB approvals had been obtained. Participant evaluations commenced on 27 Apr 2004 and ceased on 31 Oct 2006. A total of 199 patients and 55 controls (23 were newly recruited) were enrolled. There were 13 adverse events, none of which were related to the study. Computed Tomography (CT) scans were performed on 198 subjects and electroencephalographs (EEG) on 171. To date, 100 EEG and all CT reports have been received. Blood samples were collected on 252 participants for genetic analysis and 253 participants agreed to be videotaped. The National Death Index has provided information on causes of death for all Phase 2 and 3 VHIS registrants who have died and that database has been established. All participant data has been collected and entered into the VHIS master database; containing over 4500 data points per participant. All collaborators have received data sets for analysis and are currently either performing analyses or preparing manuscripts. All data has been copied and transferred to the NIH for archiving. Several presentations and manuscripts have already resulted from preliminary analyses and many more are in progress. -3 - A total of 199 patients (182 of whom participated in the Phase 2) and 55 controls (32 of whom had participated in the Phase 2; 23 were newly recruited) were enrolled. There were 13 adverse events, none of which were related to the study. Computed Tomography (CT) scans were per...

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GABAergic Deafferentation Hypothesis of Brain Aging and Alzheimer’s Disease Revisited

Cited by 87 publications

References 267 publications

Progesterone Prevents Estradiol-Induced Dendritic Spine Formation in Cultured Hippocampal Neurons

Progesterone Prevents Estradiol-Induced Dendritic Spine Formation in Cultured Hippocampal Neurons

Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer's disease and vascular dementia

Vietnam Head Injury Study - Phase III: A 30-Year Post-Injury Follow-Up Study

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