Aging is considered as the major risk factor for neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s disease (PD), constituting also the non-pathological (normal) aging process a substantial and very important part of neurological studies.
Here, we simultaneously imaged multiple metabolic pathways, including the dopaminergic, noradrenergic, serotonergic, histaminergic, and GABAergic systems, significantly altered by normal aging in detailed structures of mouse brain tissue sections by using MALDI-mass spectrometry imaging (MSI). We examined the interplay between aging and the response to tacrine-induced acetylcholinesterase (AChE) inhibition. The cholinergic system has a central role related to normal cognition and age-related cognitive decline, including dementias such as AD, where a progressive loss of limbic and neocortical cholinergic innervation is observed. Indeed, treatment with AChE increases the availability of acetylcholine (ACh) in the brain. In addition, we studied the neuropeptide and neurotransmitter system changes in animal models of PD.
Carnitine and acetylcholine/choline metabolism were the major pathways affected by aging and acetylcholinesterase inhibition in striatum, hippocampus and cortical areas. Age-related disrupted lipid metabolism was observed in striatum, cortex and specific hippocampal substructures. An age-induced increase of endogenous antioxidants, such as α-tocopherol in the hippocampus, was detected. Structure specific age-related changes were found in multiple monoaminergic pathways, e.g., dopamine and 3-methoxytyramine were found decreased in ventral pallidum, 3,4-dihydroxyphenylacetaldehyde levels were increased in caudate-putamen, and norepinephrine was decreased in hippocampus and somatosensory cortex. Using a unilateral 6-hydroxydopamine rat model of PD we simultaneously imaged >20 neuropeptides and found changes in enkephalin, dynorphin, tachykinin and neurotensin neuropeptides caused by the dopamine denervation and L-DOPA treatment in multiple brain regions.
Our comprehensive imaging approach showed significant and novel age-induced and region-specific metabolic perturbations in mitochondrial function, neurotransmission, and lipid signaling, not always attenuated by the acetylcholinesterase inhibition.