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Authors: Brewer, Gregory J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-1238

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 27-30, 2010

Authors: Barnett, Aaron | Brewer, Gregory J.

Article Type: Review Article

Abstract: Some hypothesize that aging in humans is a cumulative process of macromolecular and mitochondrial damage starting years, even decades before any symptoms arise. Aging may begin when the rate of damage exceeds the rate of continual repair and turnover. Quality control for damaged mitochondria entails cellular digestion by mitophagy, a specialized kind of autophagy. Insufficient protective autophagy could cause damaged cellular components to accumulate over many years until they affect normal function in the cell. Alternatively, aging could be the result of overactive, pathologic autophagy. Current knowledge supports both hypotheses with conflicting data, depending on which stage of autophagy is …examined. To distinguish these opposite hypotheses, two criteria need to be observed. First, is there a buildup of undigested waste that can be removed by stimulation of autophagy? Or second, if autophagy is overactive, does inhibition of autophagy rescue cell, organ and organism demise. Both of these are best determined by rate measures rather than measures at a single time point. Here, we review the generalized process of autophagy, with a focus on the limited information available for neuron mitophagy, aging, and Alzheimer's disease (AD). In two mouse models, treatment with rapamycin abolishes the AD pathology and reverses memory deficits. As a working model, we hypothesize that insufficient protective autophagy accelerates both aging and AD pathology, possibly caused by defects in autophagosome fusion with lysosomes. Show more

Keywords: Autophagosome, autophagy, beclin, lysosome mitochondrial turnover, mTOR

DOI: 10.3233/JAD-2011-101989

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 385-394, 2011

Authors: Ghosh, Debolina | Brewer, Gregory J.

Article Type: Research Article

Abstract: The extracellular redox environment of cells is mainly set by the redox couple cysteine/cystine (cys/cySS) while intracellular redox is buffered by reduced/oxidized glutathione (GSH/GSSG), but controlled by NAD(P)H/NAD(P). With aging, the extracellular redox environment shifts in the oxidized direction beyond middle-age. Since aging is the primary risk factor in Alzheimer's disease (AD), here our aim was to determine if a reduced extracellular cys/cySS redox potential of cultured primary mouse neurons changes the intracellular redox environment, affects pAkt levels, and protects against neuron loss. A reductive shift in cys/cySS in the extracellular medium of neuron cultures from young (4 month) and …old (21 month) neurons from non-transgenic) and triple transgenic AD-like mice (3xTg-AD) caused an increase in intracellular NAD(P)H and GSH levels along with lower reactive oxygen species levels. Importantly, the imposed reductive shift decreased neuron death markedly in the 21 month neurons of both genotypes. Moreover, a reduced cys/cySS redox state increased the pAkt/Akt ratio in 21 month aging and AD-like neurons that positively correlated with a decreased neuron loss. Our findings demonstrate that manipulating the extracellular redox environment toward a more reduced redox potential is neuroprotective in both aging and AD-like neurons and may be a powerful and pragmatic therapeutic tool in aging and age-related diseases like AD. Show more

Keywords: Aging, Alzheimer's disease, Akt, cys/cySS, glutathione, NAD(P)H, neurodegeneration

DOI: 10.3233/JAD-132756

Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 313-324, 2014

Authors: Dong, Yue | Brewer, Gregory J.

Article Type: Research Article

Abstract: Age and Alzheimer’s disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites …from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD+ /NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β -oxidation and glutamine. Overall age- and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD+ /NADH-dependent reactions to the increases of downstream metabolites (p  = 10-5 , n  = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P)+ /NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity. Show more

Keywords: Alzheimer’s disease, aging, citric acid cycle, dehydrogenase, energy metabolism, fatty acids, glycolysis, hippocampus, NAD, oxidation-reduction

DOI: 10.3233/JAD-190408

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 119-140, 2019

Authors: Parihar, Mordhwaj S. | Brewer, Gregory J.

Article Type: Review Article

Abstract: Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-β (Aβ) in plaques. However, an exclusively pathological role for Aβ is being challenged by new evidence for an essential function of Aβ at the synapse. Aβ protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Aβ is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Aβ at the synapse. At …physiological levels, Aβ is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Aβ40 and Aβ42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Aβ are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Aβ alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Aβ independently decrease neuronal plasticity. Our laboratory has reported that Aβ, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Aβ on synaptic plasticity. Show more

Keywords: Aging, Alzheimer's disease, mitochondria, survival signaling, synapse

DOI: 10.3233/JAD-2010-101020

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 741-763, 2010

Authors: LeVault, Kelsey R. | Tischkau, Shelley A. | Brewer, Gregory J.

Article Type: Research Article

Abstract: It is unclear whether pre-symptomatic Alzheimer’s disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2–/– model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes …during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels. Show more

Keywords: Alzheimer’s disease, APPSwDI NOS2–/–, circadian disruption, glutathione, GSH, jet lag, learning, memory, redox, sleep

DOI: 10.3233/JAD-150026

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 301-316, 2016

Authors: Struble, Robert G. | Ala, Tom | Patrylo, Peter R. | Brewer, Gregory J. | Yan, Xiao-Xin

Article Type: Review Article

Abstract: The amyloid cascade hypothesis has guided much of the research into Alzheimer's disease (AD) over the last 25 years. We argue that the hypothesis of amyloid-β (Aβ) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline in AD and the deposition of Aβ. Aβ may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis …and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population. Show more

Keywords: Amyloid-β protein, apolipoprotein E, dementia, etiology, metabolism, mitochondria, pathology, olfactory pathways, therapeutics

DOI: 10.3233/JAD-2010-100846

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 393-399, 2010

Authors: Pontrello, Crystal G. | McWhirt, Joshua M. | Glabe, Charles G. | Brewer, Gregory J.

Article Type: Research Article

Abstract: Background: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Objective: To profile the progression of pathology in AD. Methods: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. Results: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD …brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. Conclusion: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by a pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes. Show more

Keywords: Alzheimer disease, glutathione, intracellular amyloid, lifespan, mechanism, pAkt, pathogenesis, redox

DOI: 10.3233/JAD-220824

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1501-1521, 2022

Authors: Brewer, Gregory J. | Herrera, Robert A. | Philipp, Stephan | Sosna, Justyna | Reyes-Ruiz, Jorge Mauricio | Glabe, Charles G.

Article Type: Research Article

Abstract:  This work provides new insight into the age-related basis of Alzheimer’s disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic …neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45 , and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, autophagosomes, endosomes, lysosomes, mitochondria

DOI: 10.3233/JAD-190835

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 229-246, 2020