Abstract
Emerging research has re-emphasized the role of the cortical cholinergic system in the symptomology and progression of Alzheimer’s disease (AD). Basal forebrain (BF) cholinergic nuclei depend on target-derived NGF for survival during development and for the maintenance of a classical cholinergic phenotype during adulthood. In AD, BF cholinergic neurons lose their cholinergic phenotype and function, suggesting an impairment in NGF-mediated trophic support. We propose that alterations to the enzymatic pathway that controls the maturation of proNGF to mature NGF and the latter’s ulterior degradation underlie this pathological process. Indeed, the NGF metabolic pathway has been demonstrated to be impaired in AD and other amyloid pathologies, and pharmacological manipulation of NGF metabolism has consequences in vivo for both levels of proNGF/NGF and the phenotype of BF cholinergic neurons. The NGF pathway may also have potential as a biomarker of cognitive decline in AD, as its changes can predict future cognitive decline in patients with Down syndrome as they develop preclinical Alzheimer’s pathology. New evidence suggests that the cholinergic system, and by extension NGF, may have a greater role in the progression of AD than previously realized, as changes to the BF precede and predict changes to the entorhinal cortex, as anticholinergic drugs increase odds of developing AD, and as the use of donepezil can reduce rates of hippocampal and cortical thinning. These findings suggest that new, more sophisticated cholinergic therapies should be capable of preserving the basal forebrain thus having profound positive effects as treatments for AD.
Highlights
The extraordinary discovery of nerve growth factor (NGF) by Rita Levi Montalcini and Stan Cohen, under the umbrella of Victor Hamburger’s laboratory (Cohen et al, 1954; Newmark, 1986; Cowan, 2001), brought a Nobel Prize to Rita Levi-Montalcini and Stan Cohen and opened the way to the discovery of many other trophic factors and their receptors
It is well established that basal forebrain cholinergic neurons (BFCN) are highly vulnerable to Alzheimer’s disease (AD) pathology, as they are observed in greatly reduced numbers at clinical presentation (Whitehouse et al, 1981)
We demonstrated that the non-internalized, extracellular remnants are likely to be degraded by activated matrixmetalloprotease 9 (MMP-9), a process controlled by tissue inhibitor of metalloproteinases 1 (TIMP-1)
Summary
The extraordinary discovery of nerve growth factor (NGF) by Rita Levi Montalcini and Stan Cohen, under the umbrella of Victor Hamburger’s laboratory (Cohen et al, 1954; Newmark, 1986; Cowan, 2001), brought a Nobel Prize to Rita Levi-Montalcini and Stan Cohen and opened the way to the discovery of many other trophic factors and their receptors. It was demonstrated that a similar atrophy of ChAT-immunoreactive neurons, rather than cell loss, was observed in the human nucleus basalis of Meynert in AD (Pearson et al, 1983) These observations led us to propose that in AD, the primary pathology results in a secondary retrograde atrophy of cholinergic neurons of the nucleus basalis (Cuello and Sofroniew, 1984) which could be rescued by the application of exogenous mature NGF (mNGF), including the compensatory de novo cholinergic synaptogenesis of the remaining, nonlesioned, cortical tissue. When it was later demonstrated that the signal previously measured as NGF was proNGF, i.e., the NGF precursor molecule (Fahnestock et al, 2001; Peng et al, 2004), which massively predominates in the brain, it remained an open question why the BF should deteriorate when the precursor to its trophic ligand is elevated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
