Quantitative Morphometric Analysis of Basal Forebrain Neurons Expressing β-Nerve Growth Factor Receptors in Normal and Alzheimer's Disease Brains

Allen, Shelley J; Dawbarn, David; Macgowan, SH; Wilcock, GK; Treanor, Jjs; Moss, T. H.

doi:10.1159/000107132

Cited by 12 publications

(15 citation statements)

References 29 publications

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“…This loss probably reflects the loss of cholinergic neurons in this structure [1][2][3] since we have shown that these receptors are mainly expressed by cholinergic neu rons [19]. This is in agreement with the presence of NGF receptors on cholinergic neurons previously reported in this structure [15,17,22], Nevertheless, whether this loss is the event that leads to neurodegeneration remains to be determined.…”

Section: Trka-like Immunoreactivity In the Basal Forebrain O F Patiensupporting

confidence: 87%

“…In the rat [14] and in humans [15][16][17], low-affinity receptors have been described on cholinergic neurons of the nucleus basalis of Meynert, but not in the striatum or pedunculopontine nucleus. Autoradiographic studies, in the rat [14] and in humans [18], have demonstrated the presence of high-affinity l23I-NGF-binding sites (presum ably corresponding to TrkA) in the nucleus basalis of Meynert and the striatum, and their absence in the pedun culopontine nucleus.…”

Section: Introductionmentioning

confidence: 99%

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Trk Neurotrophin Receptors in Cholinergic Neurons of Patients with Alzheimer's Disease

Boissière

Hunot²,

Faucheux³

et al. 1996

Dement Geriatr Cogn Disord

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Besides cortical pathology, Alzheimer''s disease (AD) is characterized by a loss of cholinergic neurons in the basal forebrain but not in the caudate nucleus, putamen or mesencephalon. Since cholinergic neurons which degenerate in AD are sensitive to nerve growth factor (NGF), a link between NGF sensitivity and the vulnerability of cholinergic neurons has been suspected. Levels of NGF are not altered in patients with AD, however. Thus, cholinergic nerve cell death in AD could result from a deficiency in NGF receptors. Using sequential immunohistochemistry with antibodies that recognize preferentially TrkA, the specific receptor for NGF, and with antibodies directed against choline acetyltransferase we analyzed the expression of neurotrophin receptors in cholinergic neurons from control and AD brains. TrkA was expressed on cholinergic neurons of the striatum and nucleus basalis of Meynert but not on those of the mesencephalon. In AD patients, the number of neurons expressing TrkA was markedly decreased in the nucleus basalis of Meynert, very likely as a consequence of cholinergic neuronal loss. No loss of TrkA-positive neurons was observed in the striatum. Taken in conjunction with our previously published report of loss of high-affinity NGF binding in the striatum of AD patients, our results suggest a reduced expression of TrkA, the specific receptor for NGF, on striatal cholinergic neurons in AD. The loss of neurotrophin receptors may contribute to the alteration of cholinergic neurons occurring in AD.

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Section: Trka-like Immunoreactivity In the Basal Forebrain O F Patiensupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Trk Neurotrophin Receptors in Cholinergic Neurons of Patients with Alzheimer's Disease

Boissière

Hunot²,

Faucheux³

et al. 1996

Dement Geriatr Cogn Disord

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“…One study reported a substantial reduction of p75 NTR -immunoreactivity (cell area and fibre staining) in neurons of the nbM [61]. This differs from an earlier study [59] examining number and size of p75-immunoreactive ne- Both cell body and fibres are stained. The staining has a punctuate appearance and can be seen at the cell surface and also in the perinuclear region.…”

Section: Cholinergic Function and The Basal Forebrainmentioning

confidence: 68%

“…Assessment of the numbers of basal forebrain cholinergic cell bodies has revealed a wide range of loss, with largest reductions seen in early onset patients [59][60][61]. One study reported a substantial reduction of p75 NTR -immunoreactivity (cell area and fibre staining) in neurons of the nbM [61].…”

Section: Cholinergic Function and The Basal Forebrainmentioning

confidence: 99%

Clinical relevance of the neurotrophins and their receptors

2006

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The neurotrophins are growth factors required by discrete neuronal cell types for survival and maintenance, with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal. This review examines their role in diverse disease states, including Alzheimer's disease, depression, pain and asthma. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed. Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation. Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models. Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF. Conversely, in Alzheimer's disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process. This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.

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“…3 B-D (2,17,29). Interestingly, morphometric and immunohistochemical studies of the AD basal forebrain using antibodies to ChAT and nerve growth factor receptor have documented shrinkage of immunoreactive cell bodies (26,27). By using ChAT immunocytochemistry, a 25% decrease was found (26).…”

mentioning

confidence: 99%

Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants.

Holtzman

DeArmond

et al. 1992

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

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Vulnerability of specific brain regions and neuronal populations is a characteristic feature of Alzheimer disease and Down syndrome. Cholinergic neurons of the basal forebrain degenerate in both disorders. The basis for neuronal degeneration is unknown. Mouse trisomy 16 (Ts 16) is an animal model of Down syndrome. We sought an experimental system in which the survival and development of Ts 16 basal forebrain cholinergic neurons could be examined beyond the fetal period. As Ts 16 mice do not survive birth, we transplanted fetal Ts 16 and control basal forebrain into the hippocampus of young adult mice. Transplanted neurons survived and grew neurites in all grafts. Over time, we observed selective atrophy of cholinergic neurons in Ts 16 grafts. Denervation of the hippocampus produced a significant increase in the size of Ts 16 cholinergic neurons. This suggests that hippocampal-derived neurotrophic factors acted to prevent degeneration. I3/A4-amyloid-containing plaques were not seen. Ts 16 provides a model of spontaneous, genetically determined neurodegeneration that may be used to understand better the molecular pathogenesis of neuronal dysfunction in Alzheimer disease and Down syndrome.The neuropathological and neurochemical hallmarks of the Alzheimer disease (AD) brain include selective degeneration of certain neuronal populations associated with decreases in their neurotransmitter markers, loss of synapses in the neocortex, accumulation of abnormal fibrillar deposits in neurons (neurofibrillary tangles), and the deposition of amyloidcontaining plaques in the extracellular space (cerebrovascular, diffuse, and neuritic) (1-4). The principal protein component of plaques is a 39-to 42-amino acid amyloid peptide, //A4, which is derived from a larger protein, the amyloid precursor protein (APP) (5-7). The pathogenetic events leading to dementia in AD remain unclear. It is of interest that certain neuronal populations are much more severely affected than others (8). Thus, the early memory loss and intellectual decline in AD may result from the vulnerability and dysfunction of specific populations of neurons.The development of an animal model(s) of AD is critical to understanding the complex neuropathology of the disease. An animal model of Down syndrome (DS)-the trisomy 16 (Ts 16) mouse-may provide a means to study important aspects of the AD phenotype, since 100% of individuals with an extra copy of human chromosome 21 develop AD neuropathology by the fourth decade of life (9-11). Mouse chromosome 16 contains a cluster of genes and loci also located on the long arm of human chromosome 21. These include APP, superoxide dismutase (SOD1), and markers linked to one form of familial AD (12,13). Ts 16 mice demonstrate phenotypic features seen in DS including endocardial cushion defects and hematologic and immunologic abnormalities (10). In addition, the brains of these mice, as in persons with DS, are reduced in size and decreased in cortical thickness (12,14).Basal forebrain cholinergic neurons are vulnerable in ...

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Quantitative Morphometric Analysis of Basal Forebrain Neurons Expressing β-Nerve Growth Factor Receptors in Normal and Alzheimer's Disease Brains

Cited by 12 publications

References 29 publications

Trk Neurotrophin Receptors in Cholinergic Neurons of Patients with Alzheimer's Disease

Trk Neurotrophin Receptors in Cholinergic Neurons of Patients with Alzheimer's Disease

Clinical relevance of the neurotrophins and their receptors

Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants.

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