Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Abstract

Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (A␤) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of A␤ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.ABAD ͉ aging ͉ bioenergetics ͉ brain hypometabolism ͉ mitochondria T he essential role of mitochondria in cellular bioenergetics and survival has been well established (1-3). Previous studies have suggested that mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) (1, 4). Alzheimer's pathology is accompanied by a decrease in expression and activity of enzymes involved in mitochondrial bioenergetics, which would be expected to lead to compromised electron transport chain complex activity and reduced ATP synthesis (5). Further, in AD there is a generalized shift from glycolytic energy production toward use of an alternative fuel, ketone bodies. This is evidenced by a 45% reduction in cerebral glucose utilization in AD patients (6), which is paralleled by decrease in the expression of glycolytic enzymes coupled to a decrease in the activity of the pyruvate dehydrogenase (PDH) complex (5). Patients with incipient AD exhibit a utilization ratio of 2:1 glucose to alternative fuel, whereas comparably aged controls exhibit a ratio of 29:1, whereas young controls exclusively use glucose as with a ratio of 100:0 ratio (7). In addition to t...

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Multiple experimental paradigms, ranging from in vitro cell model systems and genomic analyses in animal models to postmortem autopsy of human brain and human brain imaging indicate deficits in mitochondrial function are consistent antecedents to AD development [11][12][13]24]. A decline in mitochondrial function can occur decades prior to clinical diagnosis of AD and thus may serve as a biomarker of AD risk, as well as a therapeutic target [12,24,32,67].…”

“…A decline in mitochondrial function can occur decades prior to clinical diagnosis of AD and thus may serve as a biomarker of AD risk, as well as a therapeutic target [12,24,32,67]. Preclinical in vitro and in vivo AD models have demonstrated a decline in mitochondrial function, including reduced mitochondrial respiration, decreased metabolic enzyme expression and activity, increased oxidative stress, and increased mitochondrial Aβ load and ABAD expression, prior to AD pathology [12,13,15,24,34,38]. A series of mitochondrial enhancer candidates have been proposed and investigated in preclinical and clinical studies for AD prevention and treatment ( Table 2).…”

“…Oxidative stress is primarily caused by excessive ROS produced by impaired electron transport, endoplasmic reticulum stress, and peroxisomes (Fig. 2) [24,83,98,101,102]. Decreases in enzymatic antioxidant defense capacity, including multiple superoxide dismutases (SOD), peroxiredoxins, and glutathione [103,104], further exacerbates oxidative damage [83,85,98,100].…”

“…Additionally, specific proteins are affected by mitochondrial dysfunction in AD, including amyloid precursor protein, presenilin 1 and presenilin 2, which reside along the mitochondria-associated endoplasmic reticulum membranes [23]. Decline in glucose metabolism and mitochondrial function are detected decades prior to clinical features of the disease making them potential biomarkers and therapeutic targets for prevention [12,13,24]. In vitro and in vivo preclinical AD models indicate that deficits in mitochondrial function, metabolic enzyme expression and activity, cerebral glucose metabolism, and free radical scavenging are coupled with mitochondrial Aβ load and Aβ-binding alcohol dehydrogenase (ABAD) expression [12,13,24,25].…”

“…Decline in glucose metabolism and mitochondrial function are detected decades prior to clinical features of the disease making them potential biomarkers and therapeutic targets for prevention [12,13,24]. In vitro and in vivo preclinical AD models indicate that deficits in mitochondrial function, metabolic enzyme expression and activity, cerebral glucose metabolism, and free radical scavenging are coupled with mitochondrial Aβ load and Aβ-binding alcohol dehydrogenase (ABAD) expression [12,13,24,25]. Importantly, clinical studies indicate that mitochondrial deficits observed in preclinical models are evident in human-derived platelets [14,15,[26][27][28][29].…”