Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
Degeneration of all DAergic pathways and other systems
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Although the nigrostriatal pathway is the most severely affected in PD, all
ascending DAergic pathways in the central nervous system (CNS) do degenerate
although to variable degrees (reviewed by Hornykiewicz and Kish 1987). The
mesolimbic DAergic neurons which reside adjacent to the SNpc in the VTA and
connect with the ventral striatum are less affected in PD: they are decreased between
37-50% of that in healthy subjects (Price et al. 1978, Javoy-Agid and Agid 1980, Uhl et
al. 1985, Dymecki et al. 1996). As a result, there is significantly less DA depletion in
the caudate nucleus (Price et al. 1978), the main site of projection for these neurons.
It is important to stress that PD not only affects the DAergic nerve cells of the
SN but also other areas and neurotransmitter systems: noradrenergic (locus coeruleus
(LC), where cell loss may exceed that seen in SNpc; Zarow et al. 2003), cholinergic
(nucleus basalis of Meynert, NBM; dorsal motor nucleus of vagus, DMV), and
serotonergic (dorsal raphe nuclei). Pathological changes are also observed in
glutaminergic, tryptaminergic, GABAergic, and adrenergic neurons (Braak and Braak
2000). Besides, cell loss is seen in other regions: postganglionic sympathetic neurons
and cortex (especially cingulate and entorhinal cortices), olfactory bulb, and autonomic
nervous system (Braak et al. 1995, Braak and Braak 2000, Levy 2009). Interestingly,
the loss of non-DAergic neurons, especially in the caudal brainstem, may even become
involved before the DAergic neurons (Braak et al. 2006).
Thus, PD symptoms are the consequence of progressive degeneration of the
DAergic neuronal BG system but also of other ascending subcortical neuronal systems.
Whereas the main motor manifestations of PD are linked to neurodegeneration in the
DAergic systems, the non-DAergic pathways degeneration likely contributes as a major
cause of many of the non-motor symptoms of PD, such as depression, cognitive decline,
constipation and autonomic dysfunction. As an example, degeneration of cholinergic
cortical inputs and hippocampal structures are part of the cause of the high rate of
dementia that accompanies PD, especially in older persons. As the clinical correlates of
lesions of these non-DAergic neurotransmitters pathways are not as clearly