Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease

Fukutani, Yuken; Kobayashi, Kanako; Nakamura, Ichiro; Watanabe, Kishichiro; Isaki, Kiminori; Cairns, Nigel J.

doi:10.1016/0304-3940(95)12083-g

Cited by 84 publications

(76 citation statements)

References 10 publications

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“…Apo e4 enhances the negative effects of amyloid on neurons (Mahley et al 2006) and is associated with impaired neuronal repair processes (Weisgraber and Mahley, 1996), therefore, we had assumed that its effect would be most prominent in regions with high intrinsic vulnerability to AD. Autopsy studies found CA1 to be the most severely affected hippocampal subfield in AD (West et al, 1994, Roessler et al, 2002Price et al, 2001;Fukutani et al, 1995) and therefore we had expected to find smaller CA1 volumes in AD with Apo e4 than in AD without the allele, but that was not the case. One reason for this might be that we did not have enough statistical power to detect an effect on CA1 since the number of AD subjects in our study, particularly the number of non-Apo e4 AD subjects, was small.…”

Section: Discussionmentioning

confidence: 78%

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

et al. 2008

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Background-Details of the internal hippocampal structure visible at 4T allow for in-vivo volumetry of subfields. The aims of this study were: 1. To determine if Apo e4 has subfield specific effects in controls. 2. To study the influence of Apo e4 on hippocampal subfields in AD.Methods-81 subjects (66 controls, mean age 60.8±13.6, range: 28-85 years), and 15 AD (mean age 67.5±9.3) were studied. Entorhinal cortex, subiculum, CA1, CA1-CA2 transition zone, CA3-4& dentate gyrus (CA3&DG) and total hippocampal volume were determined using a manual marking strategy.Results-Significant effects for Apo e4 on the CA3&DG were found in the total control population (p = 0.042) and in older controls (61-85 years) (p = 0.036) but not in younger (28-60 years) controls. Significant effects for Apo e4 (p = 0.0035) on CA3&DG were also found in a subgroup of older subjects and AD subjects. AD with Apo e4 had smaller CA3&DG than AD without Apo e4 (p = 0.027).Conclusions-These findings suggest that Apo e4 exerts a regionally selective effect on CA3&DG in normal aging and AD

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Section: Discussionmentioning

confidence: 78%

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

et al. 2008

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“…The DG-SGZ is a major neuroproliferative region in the adult brain and a site of increased neurogenesis in AD (9), and the nearby Ammon's horn is one of the earliest and most severely affected brain regions in AD (21,22). If injured tissue signals to neuroproliferative zones of the brain to stimulate neurogenesis, an early response in DG-SGZ might be expected for disorders, like AD, that prominently affect the hippocampus.…”

Section: Resultsmentioning

confidence: 99%

Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APP _Sw,Ind ) mice

Jin

Galván

Xie

et al. 2004

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

400

273

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Neurogenesis continues in the adult brain and is increased in certain pathological states. We reported recently that neurogenesis is enhanced in hippocampus of patients with Alzheimer's disease (AD). We now report that the effect of AD on neurogenesis can be reproduced in a transgenic mouse model. PDGF-APPSw,Ind mice, which express the Swedish and Indiana amyloid precursor protein mutations, show increased incorporation of BrdUrd and expression of immature neuronal markers in two neuroproliferative regions: the dentate gyrus and subventricular zone. These changes, consisting of Ϸ2-fold increases in the number of BrdUrdlabeled cells, were observed at age 3 months, when neuronal loss and amyloid deposition are not detected. Because enhanced neurogenesis occurs in both AD and an animal model of AD, it seems to be caused by the disease itself and not by confounding clinical factors. As neurogenesis is increased in PDGF-APPSw,Ind mice in the absence of neuronal loss, it must be triggered by more subtle disease manifestations, such as impaired neurotransmission. Enhanced neurogenesis in AD and animal models of AD suggests that neurogenesis may be a compensatory response and that measures to enhance neurogenesis further could have therapeutic potential. N eurogenesis occurs in the adult brain and can be stimulated further by pathological processes, suggesting that newly generated neurons might be capable of replacing cells that are lost in neurological diseases. Animal models have been useful in identifying and characterizing injury-induced neurogenesis associated with epilepsy (1), ischemic stroke (2), and Parkinson's disease (3). Neurogenesis triggered by ischemia in rodents, for example, is associated with migration of newborn neurons from their sites of origin in the subventricular zone (SVZ) or dentate gyrus subgranular zone (DG-SGZ) into injured areas of the brain (4-6). Neurogenesis also generates functional neurons in adult human brain (7), and increased neurogenesis has been reported in patients with Huntington's disease (8) and Alzheimer's disease (AD) (9). These findings are encouraging with respect to prospects for cell-replacement therapy because the persistent stimulus-responsiveness of neurogenesis in neurodegenerative diseases indicates that additional stimulation and regulation by therapeutic interventions may be possible.Recently, we found that neurogenesis is increased in the DG-SGZ from patients with AD (9). Compared to controls, AD brains showed increased expression of the immature neuronal markers doublecortin (DCX), embryonic nerve cell adhesion molecule, neurogenic differentiation factor Neuro D, and turned-on-after-division͞Ulip-1͞CRMP-4. Expression of DCX and turned-on-after-division͞Ulip-1͞CRMP-4 was associated with neurons in DG-SGZ, the DG granule cell layer, which is the physiological destination of these neurons, and the CA1 region of Ammon's horn, which is the principal site of hippocampal pathology in AD. These findings suggest that neurogenesis is increased in AD hippocampus, where it ...

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“…During this process, neuronal loss occurs and tau protein may be found in the extracellular space in monomeric form or in aggregated form, assembled in extracellular ghost tangles. Indeed, an inverse correlation can be found between the number of extracellular tangles and the number of living neurons in the hippocampus (3)(4)(5). It has been also suggested that extracellular aggregated tau can promote the aggregation of intracellular tau (6).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau

Dı́az-Hernández

Gómez-Ramos

Rubio

et al. 2010

Journal of Biological Chemistry

141

139

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There is solid evidence indicating that hyperphosphorylated tau protein, the main component of intracellular neurofibrillary tangles present in the brain of Alzheimer disease patients, plays a key role in progression of this disease. However, it has been recently reported that extracellular unmodified tau protein may also induce a neurotoxic effect on hippocampal neurons by activation of M1 and M3 muscarinic receptors. In the present work we show an essential component that links both effects, which is tissue-nonspecific alkaline phosphatase (TNAP). This enzyme is abundant in the central nervous system and is mainly required to keep control of extracellular levels of phosphorylated compounds. TNAP dephosphorylates the hyperphosphorylated tau protein once it is released upon neuronal death. Only the dephosphorylated tau protein behaves as an agonist of muscarinic M1 and M3 receptors, provoking a robust and sustained intracellular calcium increase finally triggering neuronal death. Interestingly, activation of muscarinic receptors by dephosphorylated tau increases the expression of TNAP in SH-SY5Y neuroblastoma cells. An increase in TNAP activity together with increases in protein and transcript levels were detected in Alzheimer disease patients when they were compared with healthy controls. Alzheimer disease (AD)3 is characterized by the loss of neurons and the presence of amyloid plaques and neurofibrillary tangles. The plaques are dense deposits of amyloid-␤ peptide and cellular material outside and around neurons, whereas the tangles are aggregates of the microtubule-associated protein tau, which has become hyperphosphorylated and accumulates inside the cells (1). In AD, tau pathology follows a reproducible pattern, in which hyperphosphorylated and aggregated tau first appears in the entorhinal cortex and hippocampus, and from there the disease spreads to the surrounding areas (2). During this process, neuronal loss occurs and tau protein may be found in the extracellular space in monomeric form or in aggregated form, assembled in extracellular ghost tangles. Indeed, an inverse correlation can be found between the number of extracellular tangles and the number of living neurons in the hippocampus (3-5). It has been also suggested that extracellular aggregated tau can promote the aggregation of intracellular tau (6). Moreover, it has been reported that extracellular monomeric tau is toxic for neurons, playing a role in the spreading of AD pathology (7-9). Monomeric tau-dependent toxicity occurs when extracellular tau binds and activates cell membrane receptors, identified as M1 and M3 muscarinic receptors (7).Sluggish disassembly of aggregated tau and slow degradation of its monomeric form in extracellular media provide this protein with a long stay outside the cell. In this location, hyperphosphorylated monomeric tau can be recognized as a substrate of several extracellular enzymes, some of which can remove the phosphates from the protein (10, 11). One of these enzymes is tissue-nonspecific alkaline phosphatas...

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Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease

Cited by 84 publications

References 10 publications

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APP _Sw,Ind ) mice

Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau

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Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease

Cited by 84 publications

References 10 publications

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APP Sw,Ind ) mice

Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau

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Product

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Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APP _Sw,Ind ) mice