Trends in Pharmacological Sciences
ReviewNerve growth factor metabolic dysfunction in Alzheimer's disease and Down syndrome
Section snippets
Alzheimer's disease and Down syndrome
Alzheimer's disease (AD) is one of the most common – and feared – age-related neurodegenerative diseases affecting world health [1]. The clinical onset of AD is characterized by the gradual loss of short-term memory followed by a progressive deterioration of cognition and behavior which may affect thinking, planning, judgment, and social skills [2]. In the end, the degree of cognitive dysfunction and physical deterioration is so pronounced that the person exhibits a profound dementia, being
Cholinergic deficits in AD and DS
Although its pathology is complex and various transmitters are affected in end-stage AD, a consistent and well-established feature of all AD brains is the presence of severe cortical cholinergic deficits, including a loss of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, in the magnitude from 50% to 90% 39, 40, 41, 42, 43, 44, 45. Such changes are also accompanied by loss of cholinergic fibers throughout the association cortex and subcortical nuclei 44, 46. As the
NGF dependency of basal forebrain cholinergic neurons
Over 80 years ago, the pioneering work of Viktor Hamburger and Rita Levi-Montalcini led to the development of the ‘neurotrophic factor hypothesis’, which states that developing neurons in the periphery and in the CNS depend on target-derived trophic factors for survival, which are retrogradely transported from their sites of production to innervating neurons [74]. These significant contributions led to the discovery of NGF 75, 76 and the subsequent identification of other members of the
The NGF metabolic pathway
The increase in proNGF in AD brains is of functional significance given that the outcome of neurotrophin action may depend on the ligand that is released, that is, the mature or immature molecule [114]. Therefore, our research team conducted classical pharmacology studies to revisit the modality of NGF release in the CNS [115]. Our investigation revealed that neither proNGF nor mature NGF were detected as released in a constitutive manner. Conversely, superfusion of cortical ex vivo tissue
NGF metabolic dysfunction in AD and MCI
Given the tight dependency of basal forebrain cholinergic neurons on endogenous NGF levels and their well-established degeneration in AD, one could hypothesize that alterations in proNGF maturation and NGF degradation should be present in this condition. Our research team analyzed the expression of proNGF and the enzymes and zymogens involved in its extracellular metabolism (i.e., tPA, plasminogen, plasmin, MMP-9, and TIMP-1) in postmortem frontal cortex tissue from AD patients and aged-matched
The NGF metabolic pathway in aging
Age-related cognitive decline is also associated with central cholinergic deficits in humans, primates, and rodents 134, 135, 136. Therefore, it would be valuable to know whether alterations in the NGF metabolic pathway would also occur in aging; particularly, because exogenous NGF administration and NGF mimetic ligands can rescue atrophic basal forebrain cholinergic neurons and the loss of cholinergic presynaptic terminations in aged animals 135, 137, 138, 139. Contrary to AD brains, aged
NGF metabolic dysfunction in DS
Given the uniformity in which adult individuals with DS acquire AD neuropathology, it follows that an NGF metabolic deregulation would ensue the development of dementia in DS. In line with previous studies in AD and MCI, postmortem brains from adult DS subjects (age range 31–68 years) exhibited a significant accumulation of proNGF in basal forebrain target tissue (in the frontal, temporal, and parietal cortex) [141]. The increase in proNGF was accompanied by alterations in the
Alterations in the NGF metabolic pathway in plasma and cerebrospinal fluid: potential new biomarkers?
Several lines of evidence suggest that proNGF accumulation and increased MMP-9 activity may represent early pathological markers signaling the presence of AD neuropathology. First, increased proNGF levels and MMP-9 activity have been reported in postmortem brains from AD and MCI patients 111, 112, 113, 129, 130, 145, and more recently in adult DS subjects with dementia [141]. Secondly, in AD and MCI, increased cortical proNGF and MMP-9 activity correlate with decreased cognitive function 129,
A link between inflammation and NGF metabolic dysfunction?
There is vast evidence in the literature indicating that proinflammatory mediators such as interleukin-1β, tumor necrosis factor-α, and nitric oxide can be potent stimulators of MMP-9 production and activation 159, 160, 161. In the McGill-Thy1-APP transgenic mouse model of AD-like amyloid pathology [162], there is evidence for proNGF accumulation, increased MMP-9 activity [112], and an early inflammatory process preceding the development of amyloid plaques [163]. This stage is also accompanied
How might NGF metabolic deficits be targeted therapeutically?
It would be desirable to search for therapeutic strategies to correct the anomalies of the NGF metabolic pathway in AD and DS. This could be conducted by facilitating the conversion of endogenous proNGF to mature NGF or by protecting the CNS from the exacerbated degradation of the biologically active neurotrophin. Such strategies should oversee therapeutic options such as delivering mature NGF directly to the CNS through intracerebroventricular infusion, via intranasal application or via the
Concluding remarks
Although the pathology of AD and DS is complex, and many neuronal populations are affected in both disorders, the atrophy and later demise of basal forebrain cholinergic neurons is of particular relevance given the role of this neuronal population in memory and attentional functions. Current cholinergic therapies offer limited symptomatic relief to patients with AD, and unfortunately there is no pharmacological approach capable of preventing the development of dementia in DS. Converging
Acknowledgments
The research described in this review was supported by a Canadian Institutes of Health Research (CIHR) grant (MOP-97776) to A.C.C. M.F.I. is the recipient of a Biomedical Doctoral Award from the Alzheimer Society of Canada. A.C.C. is the holder of the McGill University Charles E. Frosst/Merck Chair in Pharmacology. The authors wish to thank Dr A. Frosst, the Frosst family, and Merck Canada for their unrestricted support; and to honor the memory of Dr Rita Levi-Montalcini.
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