Brain Metabolic Alterations in Alzheimer’s Disease

Abstract

The brain is one of the most energy-consuming organs in the body. Satisfying such energy demand requires compartmentalized, cell-specific metabolic processes, known to be complementary and intimately coupled. Thus, the brain relies on thoroughly orchestrated energy-obtaining agents, processes and molecular features, such as the neurovascular unit, the astrocyte–neuron metabolic coupling, and the cellular distribution of energy substrate transporters. Importantly, early features of the aging process are determined by the progressive perturbation of certain processes responsible for adequate brain energy supply, resulting in brain hypometabolism. These age-related brain energy alterations are further worsened during the prodromal stages of neurodegenerative diseases, namely Alzheimer’s disease (AD), preceding the onset of clinical symptoms, and are anatomically and functionally associated with the loss of cognitive abilities. Here, we focus on concrete neuroenergetic features such as the brain’s fueling by glucose and lactate, the transporters and vascular system guaranteeing its supply, and the metabolic interactions between astrocytes and neurons, and on its neurodegenerative-related disruption. We sought to review the principles underlying the metabolic dimension of healthy and AD brains, and suggest that the integration of these concepts in the preventive, diagnostic and treatment strategies for AD is key to improving the precision of these interventions.

The Cognitive Improvement and Alleviation of Brain Hypermetabolism Caused by FFAR3 Ablation in Tg2576 Mice Is Persistent under Diet-Induced Obesity

“…Metabolic alterations are an important feature within the AD pathology [ 10 , 75 ], particularly the brain insulin resistance that has been closely tied to cognitive deficiencies [ 4 , 13 , 76 ]. Extensive literature points towards a link between T2DM, obesity, insulin resistance, and an elevated risk of developing AD and related disorders [ 77 , 78 ].…”

Transcranial alternating current stimulation combined with sound stimulation improves cognitive function in patients with Alzheimer’s disease: Study protocol for a randomized controlled trial

“…Oscillations in this band activate microglia and clear amyloid-β deposits, and this effect is only present at 40 Hz, not at other frequencies ( Iaccarino et al, 2016 ; Dhaynaut et al, 2022 ; Liu C. et al, 2022 ; Shen et al, 2022 ). Features of neurodegenerative diseases include abnormal protein aggregation, impaired protein degradation, failure of axonal transport, mitochondrial dysfunction, reduced energy metabolism, oxidative damage, and cell death ( Mattson et al, 1999 ; Ardanaz et al, 2022 ). 40 Hz-tACS can address the AD pathophysiological cascade by modulating interneuronal activity that leads to global network dysfunction and activating microglia waste removal ( Matsumoto and Ugawa, 2016 ).…”

Somatic copy number variant load in neurons of healthy controls and Alzheimer’s disease patients

“…(2) Considerable or even complete loss of NeuN immunoreactivity was also reported for neurons affected by ischemic insults (middle cerebral artery occlusion) without significant cell loss [25] or in neurons that just entered the cell death process [26]. Interestingly, these neuronal populations are of special interest because energy and nutritional deficiency and cell loss are essential characteristics of the AD brain [27]. (3) The intensity of NeuN staining is reported to be lower in AD samples [28], and further (4) due to many NeuN negative cortical neurons in FTLD-TDP (frontotemporal lobar degeneration with TDP-43 inclusions) patients, Yousef et al suggested NeuN staining as an indicator of healthy neurons [29].…”