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Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats.

Fortress AM, Buhusi M, Helke KL, Granholm AC - J Aging Res (2011)

Bottom Line: Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs).Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration.This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism of pro-NGF induced neurodegeneration in Alzheimer's disease and age-matched controls. (1) The cleavage of plasminogen to plasmin is altered due to decreased tPA from increased PAI-1 activity, leading to an accumulation of pro-NGF in the hippocampus.  (2) Increased pro-NGF leads to a preferential activation of the high affinity p75NTR/sortilin complex. (3) As NGF is down-regulated and pro-NGF is upregulated, high affinity NGF binding to TrkA receptors is compromised. (4) There is a shift in the balance of TrkA and p75NTR at the distal axon of the BFCN. (5) Pro-NGF/p75NTR/sortilin signaling increases JNK signaling and ultimately induces degeneration of the BFCNs. In age-matched controls (normal aging), balanced tPA activity allows for (1) cleavage of pro-NGF to yield NGF and (2) sustained NGF/TrkA signaling to promote cholinergic integrity. Abbreviations: tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), nerve growth factor (NGF), tropomyosin related kinase A (trkA = high affinity NGF receptor), pan neurotrophin receptor p75NTR (p75NTR = high affinity pro-NGF receptor).
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fig1: Proposed mechanism of pro-NGF induced neurodegeneration in Alzheimer's disease and age-matched controls. (1) The cleavage of plasminogen to plasmin is altered due to decreased tPA from increased PAI-1 activity, leading to an accumulation of pro-NGF in the hippocampus. (2) Increased pro-NGF leads to a preferential activation of the high affinity p75NTR/sortilin complex. (3) As NGF is down-regulated and pro-NGF is upregulated, high affinity NGF binding to TrkA receptors is compromised. (4) There is a shift in the balance of TrkA and p75NTR at the distal axon of the BFCN. (5) Pro-NGF/p75NTR/sortilin signaling increases JNK signaling and ultimately induces degeneration of the BFCNs. In age-matched controls (normal aging), balanced tPA activity allows for (1) cleavage of pro-NGF to yield NGF and (2) sustained NGF/TrkA signaling to promote cholinergic integrity. Abbreviations: tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), nerve growth factor (NGF), tropomyosin related kinase A (trkA = high affinity NGF receptor), pan neurotrophin receptor p75NTR (p75NTR = high affinity pro-NGF receptor).

Mentions: Pro-NGF, the 32 kD precursor to 14 kD mature NGF, is the predominant form of NGF in the brain [3] and is elevated in AD [3–5]. Under pathological conditions such as seizures, pro-NGF is found in astrocytes, [6] and in the case of inflammatory neuropathology, astrocytic IL-1β is able to regulate NGF secretion [7]. Pro-NGF can be cleaved intracellularly by furin or proconvertases, or extracellularly by plasmin (for review see [8]). Briefly, there are essentially two routes for NGF or pro-NGF synthesis. The first pathway results in mature NGF production: (1) pro-NGF is cleaved by plasmin to yield mature NGF that will bind with high affinity to TrkA receptors on the distal axon in the hippocampus, followed by retrograde transport in signaling endosomes to the cell body in the basal forebrain. This pathway promotes survival of the BFCNs via PI3/Akt signaling. The second signaling pathway results in the production of un-cleaved pro-NGF; (2) pro-NGF in its native state binds with high affinity to p75 receptors (p75NTR) and the co-receptor sortilin to induce cell death via the JNK pathway [9]. These two separate pathways contribute to BFCN cell survival or cell degeneration, respectively (see Figure 1).


Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats.

Fortress AM, Buhusi M, Helke KL, Granholm AC - J Aging Res (2011)

Proposed mechanism of pro-NGF induced neurodegeneration in Alzheimer's disease and age-matched controls. (1) The cleavage of plasminogen to plasmin is altered due to decreased tPA from increased PAI-1 activity, leading to an accumulation of pro-NGF in the hippocampus.  (2) Increased pro-NGF leads to a preferential activation of the high affinity p75NTR/sortilin complex. (3) As NGF is down-regulated and pro-NGF is upregulated, high affinity NGF binding to TrkA receptors is compromised. (4) There is a shift in the balance of TrkA and p75NTR at the distal axon of the BFCN. (5) Pro-NGF/p75NTR/sortilin signaling increases JNK signaling and ultimately induces degeneration of the BFCNs. In age-matched controls (normal aging), balanced tPA activity allows for (1) cleavage of pro-NGF to yield NGF and (2) sustained NGF/TrkA signaling to promote cholinergic integrity. Abbreviations: tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), nerve growth factor (NGF), tropomyosin related kinase A (trkA = high affinity NGF receptor), pan neurotrophin receptor p75NTR (p75NTR = high affinity pro-NGF receptor).
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Related In: Results  -  Collection

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fig1: Proposed mechanism of pro-NGF induced neurodegeneration in Alzheimer's disease and age-matched controls. (1) The cleavage of plasminogen to plasmin is altered due to decreased tPA from increased PAI-1 activity, leading to an accumulation of pro-NGF in the hippocampus. (2) Increased pro-NGF leads to a preferential activation of the high affinity p75NTR/sortilin complex. (3) As NGF is down-regulated and pro-NGF is upregulated, high affinity NGF binding to TrkA receptors is compromised. (4) There is a shift in the balance of TrkA and p75NTR at the distal axon of the BFCN. (5) Pro-NGF/p75NTR/sortilin signaling increases JNK signaling and ultimately induces degeneration of the BFCNs. In age-matched controls (normal aging), balanced tPA activity allows for (1) cleavage of pro-NGF to yield NGF and (2) sustained NGF/TrkA signaling to promote cholinergic integrity. Abbreviations: tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), nerve growth factor (NGF), tropomyosin related kinase A (trkA = high affinity NGF receptor), pan neurotrophin receptor p75NTR (p75NTR = high affinity pro-NGF receptor).
Mentions: Pro-NGF, the 32 kD precursor to 14 kD mature NGF, is the predominant form of NGF in the brain [3] and is elevated in AD [3–5]. Under pathological conditions such as seizures, pro-NGF is found in astrocytes, [6] and in the case of inflammatory neuropathology, astrocytic IL-1β is able to regulate NGF secretion [7]. Pro-NGF can be cleaved intracellularly by furin or proconvertases, or extracellularly by plasmin (for review see [8]). Briefly, there are essentially two routes for NGF or pro-NGF synthesis. The first pathway results in mature NGF production: (1) pro-NGF is cleaved by plasmin to yield mature NGF that will bind with high affinity to TrkA receptors on the distal axon in the hippocampus, followed by retrograde transport in signaling endosomes to the cell body in the basal forebrain. This pathway promotes survival of the BFCNs via PI3/Akt signaling. The second signaling pathway results in the production of un-cleaved pro-NGF; (2) pro-NGF in its native state binds with high affinity to p75 receptors (p75NTR) and the co-receptor sortilin to induce cell death via the JNK pathway [9]. These two separate pathways contribute to BFCN cell survival or cell degeneration, respectively (see Figure 1).

Bottom Line: Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs).Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration.This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

No MeSH data available.


Related in: MedlinePlus