Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia

Flood, Dorothy G.; Buell, Stephen J.; Horwitz, Gary J.; Coleman, Paul D.

doi:10.1016/0006-8993(87)90027-8

Cited by 159 publications

(75 citation statements)

References 35 publications

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“…The explanation we favor, however, is that estrogen may be acting indirectly on neurons projecting to dentate granule cells, such as entorhinal cortical or basal forebrain neurons that are known to have estrogen receptors (Pfaff and Keiner, 1973;L oy et al, 1988;Weiland et al, 1996). Such sensitivity to denervation and reinnervation would not be unusual for dentate granule cells and is reminiscent of their quick loss of spines because of loss of inputs during aging or disease (Nadler et al, 1973(Nadler et al, , 1977White et al, 1979;Flood and Coleman, 1986;Flood, 1987;Einstein et al, 1994;Shetty and Turner, 1995). Our finding that the brunt of the effect is carried by neurons of the dorsal blade f urther supports the hypothesis that responsivity to estrogens is caused by denervationinnervation effects because granule cells in the dorsal and ventral blades have been shown to differ in both morphology (Claiborne et al, 1990) and inputs (Amaral and Witter, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…We know already that, in the cycling female, CA1 pyramidal neurons undergo synaptic remodeling over the course of the estrous cycle but that under the same conditions dentate granule cells are unresponsive (Woolley and McEwen, 1992). However, because dentate granule cells lose spines quickly under other conditions, such as denervation caused by aging and disease (Nadler et al, 1973(Nadler et al, , 1977White et al, 1979;Flood and Coleman, 1986;Flood et al, 1987;Einstein et al, 1994;Shetty and Turner, 1995), we wondered whether they would be responsive to estrogen deprivation and replacement in the aging animal.…”

Section: Abstract: Estrogens; Aging; Alzheimer's Disease; Memory; Dementioning

confidence: 99%

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Granule Cells in Aging Rats Are Sexually Dimorphic in Their Response to Estradiol

1999

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Normal aging comprises cognitive decline, including deterioration of memory. It has been suggested that this decline in memory is sexually dimorphic because of the cessation in gonadal steroid secretion that occurs during reproductive aging in female, but not male, mammals. We wondered whether neurons in brain regions associated with learning and memory underwent morphological changes that were dimorphic as well and whether cessation of the secretion of gonadal steroids influenced these morphological changes. To explore these questions, we deprived and restored estrogens to young and old gonadectomized females and males and studied the morphology of dentate granule cells by intracellular dye filling in a lightly fixed slice preparation. We found the following: (1) Aged female dentate granule cells deprived of gonadal steroids longterm have a paucity of dendritic spines compared with young females deprived short-term; however, aged male dentate granule cells deprived of gonadal steroids long-term have no decrease in dendritic spines compared with young males deprived short-term. (2) Aged female dentate granule cells with long-term estrogen replacement at either high or low levels still had a decline in spine density. (3) Aged female dentate granule cells with short-term estradiol replacement had spine density increased to levels normally observed in young adults, whereas aged males with short-term estradiol replacement had decreased spine density. These data suggest that the response of rat dentate granule cells to aging and estradiol is sexually dimorphic and that, in females, the responsiveness of granule cells depends on the temporal pattern of estradiol replacement.

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Estrogens; Aging; Alzheimer's Disease; Memory; Dementioning

confidence: 99%

Granule Cells in Aging Rats Are Sexually Dimorphic in Their Response to Estradiol

1999

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“…For example, despite reductions in cortical thickness, unbiased stereological assessment reveals that overall neuronal number in the human brain declines Ͻ10% over the age range of 20-90 years (1), and cortical neuron and synapse numbers are relatively maintained. Although the hilus of the HC does appear to undergo mild age-related neuron loss, other hippocampal subregions show increased dendritic and synaptic complexity with increasing age (2,3), and similar synaptic remodeling is apparent in the frontal and temporal cortex (4). Alterations at the gene expression level may help account for mild cognitive decline in aging even in the absence of gross histopathologic changes.…”

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confidence: 99%

Gene expression changes in the course of normal brain aging are sexually dimorphic

Berchtold¹,

Cribbs

Coleman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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538

548

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Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20 -99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age in the superiorfrontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain and suggest that this balance is set differently in males and females, an intriguing idea.entorhinal cortex ͉ hippocampus ͉ microarray ͉ sex differences ͉ superior frontal gyrus A ging is associated with mild changes in cognitive capacity even in cognitively intact humans, including declines in memory and executive function that are associated with the hippocampus (HC) and frontal cortex. Paradoxically, these age-related changes in cognitive function are not well accounted for by corresponding age-related neuron loss and synaptic change in cortical or temporal structures. For example, despite reductions in cortical thickness, unbiased stereological assessment reveals that overall neuronal number in the human brain declines Ͻ10% over the age range of 20-90 years (1), and cortical neuron and synapse numbers are relatively maintained. Although the hilus of the HC does appear to undergo mild age-related neuron loss, other hippocampal subregions show increased dendritic and synaptic complexity with in-

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“…This hypothesis has been reinforced by evidence from transgenic (Tg) mouse models of AD in which overexpression of mutant APP results in amyloid deposition (3)(4)(5)(6)(7)(8)(9)(10). Neuritic dystrophy associated with the deposits of A␤ in AD brains is evidenced by progressive dendritic dystrophy within the hippocampal complex (11)(12)(13)(14)(15)(16)(17). Although the assumption has been that A␤ deposition leads to neuritic dystrophy that would impair hippocampal function (18,19), the causal links between the deposition and pathology have been largely inferential, with minimal data available on the time course of these events.…”

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confidence: 99%

Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses

Chawla

Games

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Increasing evidence from mouse models of Alzheimer's disease shows that overexpression of a mutant form of the amyloid precursor protein (APP) and its product, ␤-amyloid peptide, initiate pathological changes before amyloid deposition. To evaluate the cytological basis for one of these early changes, namely reduced volume of the dentate gyrus (DG), we have used high-throughput diOlistic cell loading and 3D neuronal reconstruction to investigate potential dendritic pathology of granule cells (GCs) in 90-day-old PDAPP mice. Labeled GCs from fixed hippocampal slices were selected randomly and imaged digitally by using confocal laserscanning microscopy. The dendritic complexity of GCs was quantified according to subordinate morphological parameters, including soma position within the granule cell layer (superficial versus deep) and topographic location within the DG (dorsal versus ventral blade) along the anterior-posterior hippocampal axis. Initial analysis, which included all sampled GC types, revealed a 12% reduction of total dendritic length in PDAPP mice compared with littermate controls. Further analysis, performed with refined subgroups, found that superficially located GCs in the dorsal blade were profoundly altered, exhibiting a 23% loss in total dendritic length, whereas neurons in the ventral blade were unaffected. Superficial GCs were particularly vulnerable (a 32% reduction) in the posterior region of the DG. Furthermore, the dendritic reductions of this select group were uniformly localized within middleto-outer portions of the dentate molecular layer. We conclude that substantial dendritic pathology is evident in 90-day-old PDAPP mice for a spatially defined subset of GCs well before amyloid accumulation occurs.T he classical neuropathological hallmarks of Alzheimer's disease (AD) include the presence of neurofibrillary tangles within neurons and extracellular cerebrovascular, diffuse, and neuritic plaques (1). The key molecular constituent of the plaque is ␤-amyloid (A␤), a 39-to 43-amino acid amyloidogenic peptide, which is a product of the proteolytic processing of the amyloid precursor protein (APP) (2). It has been shown that familial APP mutations may facilitate AD-like neuropathological changes by accelerating aberrant APP proteolytic processing. This hypothesis has been reinforced by evidence from transgenic (Tg) mouse models of AD in which overexpression of mutant APP results in amyloid deposition (3-10). Neuritic dystrophy associated with the deposits of A␤ in AD brains is evidenced by progressive dendritic dystrophy within the hippocampal complex (11-17). Although the assumption has been that A␤ deposition leads to neuritic dystrophy that would impair hippocampal function (18,19), the causal links between the deposition and pathology have been largely inferential, with minimal data available on the time course of these events.Tg mouse models have provided a unique opportunity to characterize A␤-induced neuropathology, including the nature and time of onset of the physiological and morpholog...

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Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia

Cited by 159 publications

References 35 publications

Granule Cells in Aging Rats Are Sexually Dimorphic in Their Response to Estradiol

Granule Cells in Aging Rats Are Sexually Dimorphic in Their Response to Estradiol

Gene expression changes in the course of normal brain aging are sexually dimorphic

Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses

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