The pontomesencephalotegmental cholinergic system does not degenerate in Alzheimer's disease

Woolf, Nancy J.; Jacobs, Roland; Butcher, Larry L.

doi:10.1016/0304-3940(89)90391-1

Cited by 100 publications

(35 citation statements)

References 15 publications

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“…A severe neuronal degeneration was observed in the basal nucleus of Meynert, locus coeruleus, the median raphe nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra, thereby confirming a number of earlier studies (Herzog and Kemper, 1980;Arendt et al, 1983;Mann et al, 1983;Shortridge et al, 1985;Yamamoto and Hirano, 1985;German et al, 1987;Jellinger, 1988;Woolf et al, 1989;Esiri et al, 1990;Goto et al, 1990;Aletrino et al, 1992;Förstl et al, 1992;Halliday et al, 1992;Scott et al, 1992). The overall extent of degeneration and the gradual variation of cell loss between different areas are also in agreement with previous reports (Zweig et al, 1988;ChanPalay et al, 1992;Arendt et al, 1995c).…”

Section: Apoe Gene Dose and Degeneration Of Subcortical Neuronssupporting

confidence: 78%

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Arendt¹,

Schindler²,

Brückner³

et al. 1997

J. Neurosci.

308

174

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A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system.In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE ⑀4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE ⑀4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE ⑀4 allele was very weak in the presence of one ⑀4 allele and completely lost in patients homozygous for the ⑀4 allele.The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE ⑀4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

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Section: Apoe Gene Dose and Degeneration Of Subcortical Neuronssupporting

confidence: 78%

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Arendt¹,

Schindler²,

Brückner³

et al. 1997

J. Neurosci.

308

174

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“…In contrast, NRA5 cells, PC12 mutants that express TrkA but not p75NGFR, showed no increase in LD50 for fAP when treated with NGF, and in fact, showed a small but statistically significant decrease (Fig. 3B) It is noteworthy that the cholinergic neurons of the basal forebrain express very high levels of p75NGFR and are affected early and severely in Alzheimer disease; in contrast, morphologically similar cholinergic neurons of the brainstem, which do not express p75NGFR, are not affected (14,15). Cortical neurons do not express p75NGFR in the normal adult primate brain but do express p75NGFR in temporal association with degeneration, both during development (23) and in Alzheimer disease (24).…”

Section: Methodsmentioning

confidence: 97%

“…NGF binding to p75NGmr inhibited the toxicity of -amyloid peptide, whereas NGF binding to TrkA, the hih-affity NGFR, enhanced it. These results suggest a possible link between 3-amybid peptide toxicity and preferential degeneration of cells expressing p75NGFR ergic complex in the mammalian brain, the pedunculopontine and laterodorsal tegmental nuclei, neither express p75NGFR nor undergo degeneration in Alzheimer disease (14,15). p75NGFR expression has been demonstrated to enhance apoptosis in the unbound state, whereas, when p75NGFR is bound by nerve growth factor (NGF) or monoclonal antibody, cell survival is enhanced (16).…”

Section: Introductionmentioning

confidence: 99%

Expression of the low-affinity nerve growth factor receptor enhances beta-amyloid peptide toxicity.

Rabizadeh

Bitler

Butcher

et al. 1994

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

118

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The low-affinity nerve growth factor receptor (NGFR) p75NGFR induces apoptosis in the absence of nerve growth factor (NGF) binding but enhances neural survival when bound by NGF. Basal forebrain cholinergic neurons express the highest levels of p75NGFR in the adult human brain and are preferentially involved in Alzhelmer disease, raising the question of whether there may be a functional relationship between the expression of p75NGFR and basal forebrain cholinergic neuronal degeneration in Alzheimer disease. The expression of p75NGFR by wild-type and mutant PC12 cells potentiated cell death induced by fi-amylold peptide. NGF binding to p75NGmr inhibited the toxicity of -amyloid peptide, whereas NGF binding to TrkA, the hih-affity NGFR, enhanced it. These results suggest a possible link between 3-amybid peptide toxicity and preferential degeneration of cells expressing p75NGFR ergic complex in the mammalian brain, the pedunculopontine and laterodorsal tegmental nuclei, neither express p75NGFR nor undergo degeneration in Alzheimer disease (14,15). p75NGFR expression has been demonstrated to enhance apoptosis in the unbound state, whereas, when p75NGFR is bound by nerve growth factor (NGF) or monoclonal antibody, cell survival is enhanced (16). Thus the effect of p75NGFR on neural cells may be analogous to that of CD40, another member of the tumor necrosis factor receptor superfamily, on centrocytes (17).Therefore, the effect of p75NGFR expression on SAP neurotoxicity was evaluated. We report that the expression of p75NGFR decreases the median lethal dose of (3AP on PC12 cell mutants by approximately one order ofmagnitude. These results suggest a possible link between SAP toxicity and preferential degeneration of cells expressing p75NGFR.

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“…A role for p75 N TR in negatively mediating cholinergic neuronal survival is suggested by the observations that p75 N TR null mutant mice display an increase in cholinergic neuron number and a decrease in developmental cell death of basal forebrain neurons (Van der Zee et al, 1996). Expression of p75 N TR also correlates with increased vulnerability of cholinergic neurons in Alzheimer's disease (Woolf et al, 1989b) and ␤-amyloid toxicity . The finding that the administration of p75 N TR antibody significantly reduced cholinergic neuron sprouting suggests a role of p75 N TR in cholinergic neurite outgrowth (LucidiPhillipi et al, 1996).…”

mentioning

confidence: 99%

Absence of p75^NTRCauses Increased Basal Forebrain Cholinergic Neuron Size, Choline Acetyltransferase Activity, and Target Innervation

et al. 1997

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Emerging evidence suggests that the p75 neurotrophin receptor (p75 NTR ) mediates cell death; however, it is not known whether p75NTR negatively regulates other neuronal phenotypes. We found that mice null for p75 NTR displayed highly significant increases in the size of basal forebrain cholinergic neurons, including those that are TrkA-positive. Cholinergic hippocampal target innervation also was increased significantly. Activity of the cholinergic neurotransmitter synthetic enzyme choline acetyltransferase (ChAT) was increased in both the medial septum and hippocampus. Upregulation of these cholinergic features was not associated with increased basal forebrain or hippocampal target NGF levels. In contrast, striatal cholinergic neurons, which do not express p75 NTR , showed no difference in neuronal number, size, or ChAT activity between wild-type and p75NTR null mutant mice. These findings indicate that p75 NTR negatively regulates cholinergic neuronal phenotype of the basal forebrain cholinergic neurons, including cell size, target innervation, and neurotransmitter synthesis.

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The pontomesencephalotegmental cholinergic system does not degenerate in Alzheimer's disease

Cited by 100 publications

References 15 publications

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Expression of the low-affinity nerve growth factor receptor enhances beta-amyloid peptide toxicity.

Absence of p75^NTRCauses Increased Basal Forebrain Cholinergic Neuron Size, Choline Acetyltransferase Activity, and Target Innervation

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The pontomesencephalotegmental cholinergic system does not degenerate in Alzheimer's disease

Cited by 100 publications

References 15 publications

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Expression of the low-affinity nerve growth factor receptor enhances beta-amyloid peptide toxicity.

Absence of p75NTRCauses Increased Basal Forebrain Cholinergic Neuron Size, Choline Acetyltransferase Activity, and Target Innervation

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Absence of p75^NTRCauses Increased Basal Forebrain Cholinergic Neuron Size, Choline Acetyltransferase Activity, and Target Innervation