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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

Aging resulted in an increase of p75NTR in the hippocampus (a) and basal forebrain (b), but only in the hippocampus was pro-NGF capable of significantly increasing p75NTR (a). Pro-NGF treatment decreased total hippocampal trkA (c) but did not significantly decrease total basal forebrain TrkA (d). Sortilin levels were not altered in the hippocampus (e) or basal forebrain (f). Changes in protein levels were normalized to β-Actin; *P ≤ .05.
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fig3: Aging resulted in an increase of p75NTR in the hippocampus (a) and basal forebrain (b), but only in the hippocampus was pro-NGF capable of significantly increasing p75NTR (a). Pro-NGF treatment decreased total hippocampal trkA (c) but did not significantly decrease total basal forebrain TrkA (d). Sortilin levels were not altered in the hippocampus (e) or basal forebrain (f). Changes in protein levels were normalized to β-Actin; *P ≤ .05.

Mentions: After Intrahippocampal injection of pro-NGF, there was a significant effect of treatment on hippocampal p75NTR receptor levels using Western blots (Figure 3(a), F2,11 = 8.374, P = .0062). Following Fisher's post-hoc analyses, aged rats exhibited significantly higher p75NTR receptor protein levels in the hippocampus than young rats when comparing the two saline injected groups (P = .0427). In addition, aged rats treated with pro-NGF had significantly greater p75NTR protein expression than aged saline-injected rats, suggesting that pro-NGF administration further aggravated age-related alterations in hippocampal p75NTR levels (P = .0395). The observed increase in p75NTR levels in the hippocampus following pro-NGF injections was not replicated in the basal forebrain, even though an overall ANOVA revealed a main effect of group in the basal forebrain for p75NTR levels (Figure 3(b), F2,11 = 5.763, P = .0194). The main effect in the basal forebrain was largely due to an increase in p75NTR receptor levels in the aged saline group compared to the young saline group (P = .0084), rather than resulting from the pro-NGF treatment.


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)

Aging resulted in an increase of p75NTR in the hippocampus (a) and basal forebrain (b), but only in the hippocampus was pro-NGF capable of significantly increasing p75NTR (a). Pro-NGF treatment decreased total hippocampal trkA (c) but did not significantly decrease total basal forebrain TrkA (d). Sortilin levels were not altered in the hippocampus (e) or basal forebrain (f). Changes in protein levels were normalized to β-Actin; *P ≤ .05.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140182&req=5

fig3: Aging resulted in an increase of p75NTR in the hippocampus (a) and basal forebrain (b), but only in the hippocampus was pro-NGF capable of significantly increasing p75NTR (a). Pro-NGF treatment decreased total hippocampal trkA (c) but did not significantly decrease total basal forebrain TrkA (d). Sortilin levels were not altered in the hippocampus (e) or basal forebrain (f). Changes in protein levels were normalized to β-Actin; *P ≤ .05.
Mentions: After Intrahippocampal injection of pro-NGF, there was a significant effect of treatment on hippocampal p75NTR receptor levels using Western blots (Figure 3(a), F2,11 = 8.374, P = .0062). Following Fisher's post-hoc analyses, aged rats exhibited significantly higher p75NTR receptor protein levels in the hippocampus than young rats when comparing the two saline injected groups (P = .0427). In addition, aged rats treated with pro-NGF had significantly greater p75NTR protein expression than aged saline-injected rats, suggesting that pro-NGF administration further aggravated age-related alterations in hippocampal p75NTR levels (P = .0395). The observed increase in p75NTR levels in the hippocampus following pro-NGF injections was not replicated in the basal forebrain, even though an overall ANOVA revealed a main effect of group in the basal forebrain for p75NTR levels (Figure 3(b), F2,11 = 5.763, P = .0194). The main effect in the basal forebrain was largely due to an increase in p75NTR receptor levels in the aged saline group compared to the young saline group (P = .0084), rather than resulting from the pro-NGF treatment.

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