Normal β-NGF content in Alzheimer's disease cerebral cortex and hippocampus

doi:10.1016/0304-3940(91)90354-V

Neuroscience Letters

Volume 131, Issue 1, 30 September 1991, Pages 135-139

https://doi.org/10.1016/0304-3940(91)90354-V Get rights and content

Abstract

Nerve growth factor (β-NGF) is known to have beneficial effects on cholinergic cell survival and to function both in vivo and in vitro. It has been speculated that this protein, or the lack of it, may be involved in the aetiology of Alzheimer's disease (AD). We describe the measurement of β-NGF content in 4 regions of the cerebral cortex and the hippocampus in AD brain compared with brain tissue from age-matched normal subjects using a sensitive sandwich immunoassay (ELISA). There was no difference in β-NGF content in any region examined in AD compared with normal values despite the marked loss of cortical cholinergic function.

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Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder, after Alzheimer’s disease. Reserpine administration to animals has been suggested as a PD model based on the effects of this monoamine-depleting agent on motor activity. Studies show that gold nanoparticles (GNPs) are effective for treating neurodegenerative diseases when used at certain concentrations. The objective of the present study was to evaluate the effects of GNPs administration under behavioral and oxidative stress conditions in an experimental model of PD. Fourty male C57BL/6 mice (20–30 g) were used, The animals were divided into four groups (N = 6): Sham; Sham and GNPs; Reserpine; Reserpine and GNPs. Three doses at the concentration of 0.25 mg/kg reserpine were administered subcutaneously at 48 h intervals. Treatment with GNPs was administered with 2.5 mg/kg GNPs (20 nm) for five consecutive days. Our results showed the therapeutic potential of GNPs, where the parameters observed in behavioral tests and oxidative stress were reverted in GNP-treated mice. It also partially improved neurotrophic factors, which are necessary for the survival of neurons. GNPs reversed the symptoms of PD caused by the use of alkaline reserpine in C57BL/6 mice, especially without toxicity. The results of this study suggest that GNPs could have clinical potential as an inhibitor of inflammation and oxidative stress in the CNS, thereby alleviating the secondary neurodegenerative processes and neuronal cell death caused by reserpine. These beneficial effects of GNPs provide support for new analyses to better understanding in the process of PD degeneration.
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Over the last decades NGF replacement intervention has become one of the potential therapeutic strategies of AD with targeted delivery showing promise [15,16,49], whereas the intracerebroventricular route is less feasible [50,51]. Neuronal (and likely even nonneuronal) cholinergic cells are greatly dependent on the NGF signaling queues for their survival and proper functioning [52,53]. Thereby the selective cholinergic degeneration occurring in the major dementia disorders, AD, and DLB [1,2] may be caused by abnormal NGF signaling [54], with the consequential decline in memory and cognitive function.
The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase.
Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed.
Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-β, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures.
A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
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Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases.
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We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process.
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The decline observed during aging involves multiple factors that influence several systems. It is the case for learning and memory processes which are severely reduced with aging. It is admitted that these cognitive effects result from impaired neuronal plasticity, which is altered in normal aging but mainly in Alzheimer disease. Neurotrophins and their receptors, notably BDNF, are expressed in brain areas exhibiting a high degree of plasticity (i.e. the hippocampus, cerebral cortex) and are considered as genuine molecular mediators of functional and morphological synaptic plasticity. Modification of BDNF and/or the expression of its receptors (TrkB.FL, TrkB.T1 and TrkB.T2) have been described during normal aging and Alzheimer disease. Interestingly, recent findings show that some physiologic or pathologic age-associated changes in the central nervous system could be offset by administration of exogenous BDNF and/or by stimulating its receptor expression. These molecules may thus represent a physiological reserve which could determine physiological or pathological aging. These data suggest that boosting the expression or activity of these endogenous protective systems may be a promising therapeutic alternative to enhance healthy aging.
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Citation Excerpt :
Nerve growth factor (NGF) is the first and best characterized member of a growth factor family (Aloe, 1989; Aloe et al., 2001; Levi-Montalcini, 1987), which includes brain-derived neurotrophic factors and neurotrophin-3 and is collectively named as neurotrophins (Sofroniew et al., 2001). NGF is critical for the differentiation of neurons during development, but also contributes to the survival and plasticity of adult forebrain cholinergic neurons (FBCN) that are known to undergo degeneration during brain aging and memory loss-related disorders, including Alzheimer disease (AD) and Parkinson disease (PD) (Allen et al., 1991; Coyle et al., 1983; Eriksdotter Jonhagen et al., 1998; Holtzman et al., 1993; Lorigados Pedre et al., 2002; Mogi et al., 1999; Muller et al., 2005; Olson et al., 1991; Seiger et al., 1993; Siegel and Chauhan, 2000). This hypothesis is supported by studies on animal models showing that endocerebral administration of NGF can rescue degenerating FBCN, while reduction of brain NGF synthesis can lead to impairment of neuronal plasticity and memory deficits (Conner and Dragunow, 1998; Liberini and Cuello, 1994; Sofroniew et al., 2001).
It has been shown that conjunctivally applied NGF in rats can reach the retina and optic nerve. Whether topical eye NGF application reaches the central nervous system is not known. In the present study, we have addressed this question. It was found that topical eye NGF application affects brain cells. Time-course studies revealed that repeated NGF application leads to high concentration of this neurotrophins after 6 h and normal levels after 24 h. Our results also showed that topical eye application of NGF causes an enhanced expression of NGF receptors and ChAT immunoreactivity in forebrain cholinergic neurons, suggesting that ocular NGF application could have a functional role on damaged brain cells. The present findings suggest that eye NGF application can represent an alternative route to prevent degeneration of NGF-receptive neurons involved in disorders such as Alzheimer and Parkinson.

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Normal β-NGF content in Alzheimer's disease cerebral cortex and hippocampus

Abstract

Exp. Neurol.

Lancet

Brain Res.

Neurosci. Lett.

Brain Res.

Mol. Brain Res.

Brain Res.

Exp. Neurol.

Neurobiol. Aging

Mol. Brain Res.

Exp. Neurol.

Neuroscience

Brain Res.

Neurosci. Lett.

Distribution of β-nerve growth factor receptors in the human basal forebrain

J. Comp. Neurol.

A quantitative morphometric analysis of basal forebrain neurons expressing β-NGF receptors in normal and Alzheimer's disease brains

Dementia

Distribution and characterization of β-nerve growth factor receptors in Alzheimer's disease