High resilience of human cerebellum in Alzheimer's disease: reciprocal coupling of cellular anabolic and catabolic fluxes enable intensive neuroprotection.

UNLABELLED

We elucidate that the cerebellum displays striking resilience to neurodegenerative changes under aging or Alzheimer's disease (AD). We identify the neurobiological factors that underlie the natural neuroprotective characteristic of cerebellum, thereby obtaining innovative therapeutic directions that may duplicate this naturalistic neurorestorative response. We investigated the mass spectrometry/liquid chromatography-based proteomics profile from AD tissue: sparely affected cerebellum and highly affected hippocampus/cingulate/entorhinal cortex. We found 83 upregulated and 37 downregulated cerebellar genes. Top five upregulated genes were (hub-gene), these encode for neurorestorative processes, as axonal, dendritic, and myelination growth. Contrastingly, the top five downregulated genes were (hub-gene), . These encode for NADH-dehydrogenase subunit in mitochondria; their increased expression relates to mitochondrial-based ROS stress-based apoptosis; hence, their downregulation reduces apoptosis, reinforcing neural survival. Indeed, cerebellum displays unique neuroprotection, by coupling of two reciprocal cytometabolic fluxes: (1) hyperactivation of neural anabolic processing, as neuronal growth, and (2) hypoactivation of neural catabolic processing, as mitochondrial caspase-induced neural degradation. Hence, for inducing the endogenous neuroprotective response, one needs to pharmacologically modulate both these cytometabolic processes: (i) agonism of neural synaptotropic anabolic pathway, coupled to (ii) antagonism of mitochondrial catabolic neurotoxic pathway. We also observed that synaptic efficiency-encoding genes constitute majority (70%) of upregulated cerebellar genes. We noted the unexpected observations, namely that (a) the neuron is the most pivotal factor for the restorative response than any type of glial or other cells, (b) with respect to the neuron, the synaptogenesis process is much more critical than the neurogenesis process, and (c) collaterally, the hypomodulation of the mitochondrial NADHD ubiquinone activity is the key factor. A unique significance is that a naturally occurring neurorestorative response may be therapeutically harnessed in neurons, minimizing off-target effects that are often hazardous disadvantages of conventional dementia therapeutics.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s13205-025-04264-y.