Cortical abnormalities in Alzheimer's disease

Foster, Norman L.; Chase, Thomas N.; Mansi, Luigi; Brooks, Rodney A.; Fedio, Paul; Patronas, Nicholas J.; Chiro, Giovanni Di

doi:10.1002/ana.410160605

Cited by 361 publications

(130 citation statements)

References 34 publications

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“…Glucose is the brain's main energy substrate, providing energy to make ATP to maintain ion gradients, synaptic transmission, protein synthesis (for review, see Hoyer, 1996), and fatty acid turnover in membranes phospholipids (Rapoport et al, 2001). A decline in cerebral glucose metabolism is widely reported in AD (Foster et al, 1984;Blennow et al, 2006;Mosconi et al, 2007). This deterioration in brain fuel supply is progressive, correlates broadly with dementia severity, and may appear during normal aging at which time there can be an approximately 6% reduction in glucose uptake per decade (Petit-Taboué et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Tremblay‐Mercier¹,

Tessier²,

Plourde³

et al. 2010

J Pharmacol Exp Ther

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Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferatoractivated receptor (PPAR)-␣ agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 Ϯ 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). ␤-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid ␤-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-13 C]linoleic acid. As expected, 12weeks on bezafibrate decreased plasma triglycerides by 35%. Bezafibrate tended to raise postprandial ␤-hydroxybutyrate, an effect that was significant after normalization to the fasting baseline values (p ϭ 0.03). ␤-Oxidation of [U-13 C]linoleic acid increased by 30% (p ϭ 0.03) after treatment. On the metabolic study day after bezafibrate treatment, postprandial insulin decreased by 26% (p ϭ 0.01), and glucose concentrations were lower 2 to 5 h postprandially. Thus, in hypertriglyceridemic individuals, bezafibrate is mildly ketogenic and significantly changes fatty acid metabolism, effects that may be linked to PPAR␣ stimulation and to moderately improved glucose metabolism.As the population ages, the prevalence of cognitive impairment in the elderly, particularly Alzheimer's disease (AD), is increasing markedly. Glucose is the brain's main energy substrate, providing energy to make ATP to maintain ion gradients, synaptic transmission, protein synthesis (for review, see Hoyer, 1996), and fatty acid turnover in membranes phospholipids (Rapoport et al., 2001). A decline in cerebral glucose metabolism is widely reported in AD (Foster et al., 1984;Blennow et al., 2006;Mosconi et al., 2007). This deterioration in brain fuel supply is progressive, correlates broadly with dementia severity, and may appear during normal aging at which time there can be an approximately 6% reduction in glucose uptake per decade (Petit-Taboué et al., 1998). Reduced brain glucose metabolism can arise before the clinical symptoms of AD (Reiman et al., 2004) and may contribute to neurodegenerative processes leading to AD (Liu 2004(Liu , 2008. As such, an alternative brain fuel to glucose may be therapeutically useful in AD.Physiologically, ketone bodies [or ketones; ␤-hydroxybutyrate (␤-OHB), acetoacetate, and acetone] are the main alternative energy substrate to glucose for brain metabolism and are especially important during periods of glucose deprivation. Ketones can supply up to two thirds of the energy requirement of the brain during starvation (Owen et al., 1967). Mildly increasing ketone synthesis has been proposed as a possible therapeutic approach to correct or bypass brain

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Section: Introductionmentioning

confidence: 99%

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Tremblay‐Mercier¹,

Tessier²,

Plourde³

et al. 2010

J Pharmacol Exp Ther

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“…In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1,4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5,6).…”

mentioning

confidence: 99%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

143

101

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Accumulation of amyloid ␤ (A␤) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of A␤. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied A␤ oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to A␤ aggregation and subsequent synaptic loss.Abnormal protein misfolding and aggregation are common features in neurodegenerative diseases such as Alzheimer (AD), 2 Parkinson, Huntington, and prion diseases (1-3). In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1, 4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5, 6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons. The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.A␤ accumulation and aggregation could derive from overproduction or impaired clearance. Mutations of APP or presenilins 1 and 2, for example, are shown to cause overproduction of A␤1-42 and amyloid deposits in the brain of early onset AD (18,19). Because early onset AD accounts for less than 5% of entire AD population, APP and presenilin mutati...

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“…Cortical hypometabolism (e.g., de Leon et al, 1983;Foster et al, 1984;Friedland et al, 1989;Grady et al, 1988;Ibáñez et al, 1998) and NFTs (Braak & Braak, 1991;Delacourte et al, 1999) can also be found throughout temporal, parietal, and frontal cortex in individuals with AD.…”

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confidence: 99%

When memory does not fail: Familiarity-based recognition in mild cognitive impairment and Alzheimer's disease.

et al. 2006

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Recognition can be guided by familiarity, a restricted form of retrieval devoid of contextual recall, or by recollection, which occurs when retrieval is sufficient to support the full experience of remembering an episode. Recollection and familiarity were disentangled by testing recognition memory using silhouette object drawings, high target-foil resemblance, and both yes-no and forced-choice procedures. Theoretically, forced-choice recognition could be mediated by familiarity alone. Alzheimer's disease and its preclinical stage, mild cognitive impairment (MCI), were associated with memory impairments that were greater on the yes-no test. Remarkably, forced-choice recognition was unequivocally normal in patients with MCI compared with age-matched controls. Neuropathology in hippocampus and entorhinal cortex, known to be present in MCI, presumably disrupted recollection while leaving familiarity-based recognition intact.

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Cortical abnormalities in Alzheimer's disease

Cited by 361 publications

References 34 publications

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

When memory does not fail: Familiarity-based recognition in mild cognitive impairment and Alzheimer's disease.

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