In a new study published in Free Radical Biology and Medicine, researchers have identified a link between mitochondrial function and the vulnerability of specific brain regions to age-associated neurodegeneration .
Brain region-specific vulnerability
It is well-known that the human brain is heterogeneous in terms of structure and function. The prefrontal cortex is responsible for complex cognitive behavior, the hippocampus is the major memory center, the cerebellum is the motor control center, and the brain stem controls automatic functions such as breathing.
Age-associated neurodegenerative diseases are characterized by neurodegeneration in specific brain regions. Thus, neuronal loss in the hippocampus seen in Alzheimer’s disease underlies the resulting memory loss, while basal ganglia neurodegeneration is responsible for the motor dysfunction in Parkinson’s disease and Huntington’s disease.
The mechanisms underlying aging-related brain region-specific neuronal vulnerability are unclear. If the physiological basis for such heterogeneity were known, it would be possible to selectively target these vulnerable regions to prevent neurodegeneration. For example, region-specific neuromodulation was recently shown to be a successful approach.
Previous studies have shown that mitochondrial dysfunction plays an important role in neurodegeneration. However, the connection between mitochondrial deficits and brain region-specific vulnerability to neuronal loss has not been investigated.
In this study, the researchers hypothesized that young age brain regions differ in their baseline mitochondrial function, which, when exaggerated with age, leads to disease. They analyzed post-mortem human brain specimens of different ages to verify that their conclusions are directly applicable to human physiology.
Mitochondrial activity differences
The researchers analyzed the brains of neurological disease-free males of the following age groups: early young (1-19), adult (20-39), middle-aged (40–59), and old (60–90).
First, they assessed the mitochondrial activity (several protein complexes) of five brain regions: the frontal cortex, striatum (a basal ganglia structure), hippocampus, cerebellum, and medulla oblongata (a brainstem structure).
The analysis showed that the activity of the mitochondrial complexes differs significantly across the five brain regions at young ages, which is sustained at older ages. Interestingly, the medulla is characterized by the highest mitochondrial activity, hinting at a possible explanation of the relative neurodegeneration resistance of this region.
Next, the researchers compared the mitochondrial proteome across the five regions and ages. This analysis revealed a high degree of similarity between the frontal cortex, striatum, and hippocampus of both young and old people. The cerebellum and medulla were similar to each other but quite different from the former three. With age, the most dramatic protein expression change was observed in the striatum and cerebellum, and the least was in the medulla.
A functional analysis of the genes differentially expressed in the young brains showed that the medulla is characterized by the enrichment of mitochondrial and antioxidant proteins compared to other regions, which were enriched with proteins involved in synaptic processes instead. These differences were mostly sustained with age.
The results of the following analysis of the protein phosphorylation profile of the five brain regions were mostly in line with previously obtained data: the cerebellum and medulla were distinct from the other three regions. Microtubule-associated protein tau (MAPT) was of particular interest, as phosphorylated MAPT is associated with neurodegeneration and was found hyperphosphorylated and overexpressed in the frontal cortex and hippocampus with age.
“Last in, first out”
The results of this study are in line with the so-called “last in, first out” hypothesis of aging: the most recent to develop (both from the evolutionary and the developmental point of view) brain regions are the first to undergo neurodegeneration. Indeed, the cerebellum and medulla, more ancient parts, seem less vulnerable to neuronal loss compared to the more recent brain regions, such as the frontal cortex and hippocampus.
The vulnerability or resistance of certain brain regions to neurodegeneration is associated with the expression of neuroprotective proteins. The brain regions that are characterized by the enrichment of mitochondrial and antioxidant proteins as well as some other pro-longevity hub proteins are less vulnerable.
Selective neuronal vulnerability (SNV) of specific neuroanatomical regions such as frontal cortex (FC) and hippocampus (HC) is characteristic of age-associated neurodegenerative diseases (NDDs), although its pathogenetic basis remains unresolved. We hypothesized that physiological differences in mitochondrial function in neuroanatomical regions could contribute to SNV. To investigate this, we evaluated mitochondrial function in human brains (age range:1–90 y) in FC, striatum (ST), HC, cerebellum (CB) and medulla oblongata (MD), using enzyme assays and quantitative proteomics. Striking differences were noted in resistant regions- MD and CB compared to vulnerable regions- FC, HC and ST. At younger age (25 ± 5 y), higher activity of electron transport chain enzymes and upregulation of metabolic and antioxidant proteins were noted in MD compared to FC and HC, that was sustained with increasing age (≥65 y). In contrast, the expression of synaptic proteins was higher in FC, HC and ST (vs. MD). In line with this, quantitative phospho-proteomics revealed activation of upstream regulators (ERS, PPARα) of mitochondrial metabolism and inhibition of synaptic pathways in MD. Microtubule Associated Protein Tau (MAPT) showed overexpression in FC, HC and ST both in young and older age (vs. MD). MAPT hyperphosphorylation and the activation of its kinases were noted in FC and HC with age. Our study demonstrates that regional heterogeneity in mitochondrial and other cellular functions contribute to SNV and protect regions such as MD, while rendering FC and HC vulnerable to NDDs. The findings also support the “last in, first out” hypothesis of ageing, wherein regions such as FC, that are the most recent to develop phylogenetically and ontogenetically, are the first to be affected in ageing and NDDs.
This study is the first comprehensive analysis of age-associated brain region-specific vulnerability to neurodegeneration in humans. Although it showed the differences in mitochondrial function across different brain regions, additional functional analyses are required to confirm its role in region-specific vulnerabilities to neurodegeneration. Moreover, only male brains were used in this study, calling for additional studies to explore if these results are applicable to the female brain.
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 Anusha-Kiran, Y. et al. Regional heterogeneity in mitochondrial function underlies region specific vulnerability in human brain ageing: Implications for neurodegeneration. Free Radical Biology and Medicine (2022) doi:10.1016/j.freeradbiomed.2022.09.027