Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease

Abstract

ObjectiveIncreasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD.MethodsThe study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [11C]PiB and [18F]florzolotau, respectively. Myo‐inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography.ResultsMyo‐inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo‐inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo‐inositol and lactate levels were positively associated with the Clinical Dementia Rating sum‐of‐boxes scores (p < 0.05). Significant correlations were noted between myo‐inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05).InterpretationWe found high myo‐inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo‐inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2023

Decreased brain pH correlated with progression of Alzheimer’s disease neuropathology: a systematic review and meta-analyses of postmortem studies

“…Indeed, hyperexcitation in certain neurons and/or neural circuits has been suggested in the etiology of AD (Busche and Konnerth, 2016;Murano et al, 2019;Maestú et al, 2021). Furthermore, an increase in brain (Mullins et al, 2018;Hirata et al, 2024) and 1 1 CSF (Liguori et al, 2015(Liguori et al, , 2016 lactate levels has been observed in patients with AD compared to control subjects. Neuronal hyperexcitation (Palop et al, 2007;You et al, 2017) and increased brain lactate and decreased brain pH levels (Hagihara et al, 2024) have been observed in a well-known mouse model of AD harboring the human amyloid precursor protein (APP) mutant allele that is linked to familial AD.…”

“…A decrease in brain pH is suggested to be associated with an increase in lactate level under these psychiatric disorders (Prabakaran et al, 2004; Stork and Renshaw, 2005; Halim et al, 2008), which could be due to metabolic changes resulting from mitochondrial dysfunction and/or increased glycolysis due to neuronal hyperexcitation. An increase in brain (Mullins et al, 2018; Hirata et al, 2024) and CSF (Liguori et al, 2015, 2016) lactate levels has been observed in patients with AD compared to control subjects, suggesting common metabolic alterations and neuronal hyperexcitability across such psychiatric and neurodegenerative disorders.…”

In vivoassessment of astrocyte reactivity in patients with progressive supranuclear palsy

“…17 Elevated lactate levels have also been discovered in the brain and CSF of patients with AD and other neuropsychiatric disorders. 11,59,60 Furthermore, a study involving various mouse models of neuropsychiatric disorders demonstrated a correlation between elevated brain lactate levels and cognitive decline. 61 These findings indicate that lactate may play a role in the pathophysiology of various neuropsychiatric disorders.…”

“…The use of myo-inositol, a metabolite detectable by MRS, holds promise for the assessment of astrocyte reactivity. 10,11 This metabolite, which mainly found in glial cells, is reportedly elevated in reactive astrogliosis. 12–14 In patients with AD, increased myo-inositol levels in the posterior cingulate cortex (PCC) region, a hub of the default mode network (DMN), are reportedly noted from the early stages of the disease.…”

“…24 We recently demonstrated increased lactate levels in the PCC and their association with increased myo-inositol levels by using an advanced MRS sequence in patients with AD. 11 This study used the same MRS technique to quantify both lactate and myo-inositol levels in the ACC to investigate the potential impact of reactive astrocytes on changes in brain energy metabolism in PSP.…”