Interplay between the catecholaminergic enzymatic axis and neurodegeneration/neuroinflammation processes in the Alzheimer's disease continuum

Background and Purpose: The locus coeruleus (LC) provides dopamine/noradrena- line (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebro- spinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes.Methods: The CSF concentration of DA transporter (DAT), tyrosine-hydroxylase (TH), DOPA-decarboxylase (DDC), and dopamine-beta- hydroxylase (D beta H), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta-amyloid (A beta)1-42 (A) and p -tau (T) in AD pathological changes (A+ T-) and AD (A+ T+) subgroups, as well as in 15 control subjects (A- T-).Results: The ADc group had lower CSF levels of DAT and TH but increased D beta H levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but com- parable with controls in the A+ T- subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and A beta 1-42 (R2 = 0.25) and between DDC and p -tau (R2 = 0.33). Finally, TH correlated with interleukin (IL) -10 levels (p = 0.0008) and D beta H with IL- 1 beta (p = 0.03), IL -4 (p = 0.02), granulocyte colony-stimulating factor (p = 0.007), and IL -17 (p = 0.01).Conclusions: Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurode- generative and neuroinflammatory processes in AD pathology.

Automated summary

The levels of catecholaminergic enzymes in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) were analyzed. It was found that AD patients had lower levels of dopamine/norepinephrine (DA/NA) innervation markers, but increased levels of dopamine-beta-hydroxylase (D beta H). These findings indicate a close association between catecholaminergic enzymes and the neurodegenerative and neuroinflammatory processes in AD pathology.