**4. Comparison of the consequence of LC neuronal loss between PD and Alzheimer's disease (AD)**

#### **4.1 Alterations in terminal noradrenergic markers**

Alzheimer's disease (AD), another neurodegenerative disorder, also exhibits significant LC noradrenergic neuronal loss (Bondareff et al., 1982; Chan-Palay & Asan, 1989; German et al., 1992; Mann et al., 1980; Marcyniuk et al., 1986; Szot et al., 2000, 2006; Tomlinson et al., 1981). However, unlike PD, in AD subjects the surviving LC noradrenergic neurons appear to be compensating for the loss. The content of NE in terminal regions of postmortem AD subjects is reduced, but the reduction does not correspond to the degree of neuronal loss (Adolfsson et al., 1979; Hoogendijk et al., 1999; Mann et al., 1981; Palmer et al., 1987; Reinikainen et al., 1988; Toghi et al., 1992; Tomlinson et al., 1981). Similar results were observed for IR of NE-synthesizing enzymes in the forebrain of postmortem AD subjects (Cross et al., 1981; Palmer et al., 1987; Perry et al., 1981; Russo-Neustadt et al., 1998). These data indicate that there is a reduction in NE function in forebrain regions of AD subjects, but it doesn't correlate to the degree of LC neuronal loss even in a region like the cortex which receives all of its innervation from the LC (Aston-Jones et al., 1995; Jones & Moore, 1977; Loughlin et al., 1986a, b; Mason & Fibiger, 1970; Moore & Bloom, 1979; Olsen & Fuxe, 1971; Ungerstedt, 1971; Waterhouse et al., 1983). These data suggest the surviving LC noradrenergic neurons in AD may be compensating for the lost neurons.

The Noradrenergic System is a Major Component in Parkinson's Disease 253

indicated above), but in subjects with dementia where TH mRNA expression/neuron is elevated, DBH mRNA expression/neuron is not different from controls (McMillan et al., 2011). This suggests that the loss of LC noradrenergic neurons does not necessarily result in increased DBH mRNA expression/neuron. Compensation of the LC noradrenergic nervous system in AD subjects is also observed in CSF NE levels, where CSF NE levels are similar to or elevated to age-matched control subjects (Elrod et al., 1997; Gottfries et al., 1983; Mann et

It appears then the response of surviving LC noradrenergic neurons in AD, in regards to the noradrenergic markers measured, is completely different from the response of surviving LC noradrenergic neurons in PD (Table 1). These noradrenergic markers in AD suggest that noradrenergic function in AD subjects may not be reduced and may even exceed function in normal subjects, while in PD subject's noradrenergic function is reduced. This hypothesis is supported clinically. Orthostatic hypotension, a common non-motor symptom observed in PD due to reduced noradrenergic function, is not observed in AD subjects despite a similar degree of LC noradrenergic neuronal loss. A progression of noradrenergic function can be drawn between these two neurodegenerative disorders; at one of the spectrum PD represents the loss of LC noradrenergic neurons with reduced noradrenergic function, while AD represents the other end of the spectrum with the loss of LC noradrenergic neurons but

As indicated above, LC noradrenergic neurons are reduced early in the progression of PD (Braak et al., 2003b, 2006). However, for the noradrenergic system to be involved in the progression of PD, LC noradrenergic neurons need to innervate the regions involved in the symptoms of PD (i.e., striatum and SN). There is evidence to indicate that the LC noradrenergic nervous system can modulate dopaminergic activity at the level of the striatum and the SN as well as the ventral tegmental area (VTA) at the anatomical,

LC noradrenergic neurons have direct projections to the striatum, though evidence indicates this innervation may be sparse (Aston-Jones et al., 1995; Jones & Moore, 1977; Jones & Yang, 1985; Mason & Fibiger, 1979; Swanson & Hartman, 1975). When measured, NE concentration in the striatum is low (especially compared to DA), while NET binding (a marker of noradrenergic terminals) is not detectable (Szot, Personal communication; Koob et al., 1975; Nomura et al., 1976). However, the striatum does contain a dense amount of betaadrenergic receptors (β-AR) (Byland & Snyder, 1976; Dolphin et al., 1979; Rainbow et al., 1984; Strazielle et al., 1999), as well as alpha2-AR (α2-AR) (Szot, Personal communication; Boyajian et al., 1987; Hudson et al., 1992; Nicholas et al., 1992; Scheinin et al., 1994; Strazielle et al., 1999; Zeng and Lynch, 1991) and alpha1-AR (α1-AR) (Szot, Personal communication; Rommelfanger et al., 2009; Strazielle et al., 1999) binding sites. Direct application of NE or administration of AR agents can affect the activity of striatal neurons and release of DA in

al., 1981; Raskind et al., 1984; Toghi et al., 1992).

enhanced noradrenergic function.

**5.1 LC innervation to striatum** 

**5. LC innervation of dopaminergic regions** 

electrophysiological, neurochemical, and behavioral levels.

the striatum (Bevam et al., 1975; Fujimoto et al., 1981; Lategan et al., 1990).

**4.3 Summary** 

#### **4.2 Alterations in noradrenergic markers in LC**

To determine if the surviving LC noradrenergic neurons in AD subjects are demonstrating compensatory changes, several noradrenergic markers, similar to the markers used on the LC tissue of PD subjects, were assessed in the LC of subjects with AD. Work from my laboratory showed that the surviving noradrenergic neurons in the LC of AD and a related dementing disorder, dementia with Lewy body (DLB), showed compensatory changes. In subjects with dementia, the number of TH, DBH and NET mRNA positively labeled neurons in the LC are significantly reduced as compared to age-matched control subjects (Szot et al., 2000, 2006) and the degree of this LC neuronal loss corresponds to documented loss of noradrenergic neurons in AD by other laboratories (Bondareff et al., 1982; Chan-Palay & Asan, 1989; German et al., 1992; Mann et al., 1980; Marcyniuk et al., 1986; Tomlinson et al., 1981). The degree of LC noradrenergic neuronal loss determined by TH mRNA expression in AD subjects is verified by counting the number of TH-IR positive labeled neurons (McMillan et al., 2011).


Table 1. Changes in noradrenergic markers in the LC of PD subjects and subjects with dementia as compared to appropriate control groups.

However, in AD, the surviving LC noradrenergic neurons exhibit increased TH mRNA expression/neuron as compared to age-matched control subjects (Szot et al., 2000, 2006), suggesting compensation. NET binding over cell body region in the LC of AD subjects is significantly reduced as compared to age-matched control subjects, and the loss of NET binding over the cell body region corresponds to the number of LC noradrenergic neurons in the LC (Szot et al., 2006). However, NET binding sites over the peri-LC dendritic zone in AD subjects is not significantly different from age-matched control subjects, despite the reduction in LC noradrenergic neurons positively labeled for NET mRNA (Szot et al., 2000, 2006). The normal amount of NET binding in the peri-LC dendritic zone of AD subjects indicates dendritic sprouting of the surviving LC neurons. TH-IR labeling in dendritic region of AD supports the notion of enhanced dendritic innervation around LC noradrenergic neurons in AD subjects observed with NET binding (McMillan et al., 2011), again indicating compensation of the surviving LC neurons in AD. In addition to the sprouting in the LC, the surviving LC neurons in AD exhibit axonal sprouting into the hippocampus and prefrontal cortex (Szot et al., 2006, 2007). The difference in the response of the surviving LC noradrenergic neurons in PD and AD is observed even concerning DBH mRNA expression/neuron. In PD, DBH mRNA expression/neuron is elevated (as indicated above), but in subjects with dementia where TH mRNA expression/neuron is elevated, DBH mRNA expression/neuron is not different from controls (McMillan et al., 2011). This suggests that the loss of LC noradrenergic neurons does not necessarily result in increased DBH mRNA expression/neuron. Compensation of the LC noradrenergic nervous system in AD subjects is also observed in CSF NE levels, where CSF NE levels are similar to or elevated to age-matched control subjects (Elrod et al., 1997; Gottfries et al., 1983; Mann et al., 1981; Raskind et al., 1984; Toghi et al., 1992).
