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Papers by john carney

2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclos... more 2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclosed. These materials are useful as pharmaceutical agents for oral or parenteral. e.g. intravenous administration to patients su?'ering from acute central nervous system oxidation as occurs in a stroke or from gradual central nervous system oxidation which can exhibit itself as progressive central nervous system function loss. The materials are also used to ameliorate the side elfects of oxidative-damage causing antineoplastic disease treatments.

Pharmacology Biochemistry and Behavior, 1976

Variable interval responding maintained by intravenous codeine and ethanol injections in the rhes... more Variable interval responding maintained by intravenous codeine and ethanol injections in the rhesus monkey. PHARMAC. BIOCHEM. BEHAV. 5(5) 577-582, 1976.-Rhesus monkeys were trained to respond under a variable interval 2 min schedule for codeine or ethanol injections. Both codeine and ethanol were effective in the initiation of variable-interval responding; responding was maintained over a range of codeine (0.003-1.0 mg/kg/injection) and ethanol doses (32.0-560 mg/kg/injeetion). Maximum rates of responding were obtained at the 0.01 mg/kg/injection codeine dose (0.14 responses/see) and at the 180 mg/kg/injection codeine dose (0.19 responses/sec). Rates of responsing were bitonic functions of the reinforcer dose for both codeine and ethanol; maximum rates were obtained at intermediate doses and lower rates occurred at the extremes of the dose range. Both codeine and ethanol showed within-session decreases in responding across the range of reinforcer doses. Codeine-reinforced responding declined in rate within the one-hour session without a similar change in the frequency of drug injection; in contrast, both ethanol-reinforced responding and the frequency of ethanol injections declined within each session across a range of doses. Increasing or decreasing the codeine dose halfway through the one-hour session resulted in increases or decreases in codeine responding compared to controls. These data indicate that the progressive decline in codeine-reinforced responding is not the result of a generalized disruption of responding.

Free Radicals and Aging, 1992

During aging a number of enzymes accumulate as catalytically inactive or less active forms. The a... more During aging a number of enzymes accumulate as catalytically inactive or less active forms. The age-related changes in catalytic activity are due in part to reactions of the protein with "active" oxygen species such as ozone, singlet oxygen, or with oxygen free radicals as are produced during exposure to ionizing radiation or to metal ion catalyzed oxidation (MCO) systems. The levels of oxidized proteins in cultured human fibroblasts from individuals of various ages and in liver and brain extracts of rats of different ages increase progressively with age, and in old rats can represent 30-50% of the total cellular protein. The age-related increase in oxidized protein in rat liver and brain tissue is accompanied by a loss of glutamine synthetase (OS) and glucose-6-P dehydrogenase (0-6-PDH) activities, and to a decrease in the level of cytosolic neutral protease activity which is responsible for the degradation of oxidized (denatured) protein. Of particular significance are the results of experiments showing that similar age-related changes occur in the gerbil brain and that these changes are accompanied by a loss of short-term memory as measured by the radial arm maze technique. Chronic treatment (intraperitoneal injections) of old animals with the free ~adical spin-trap reagent, N-tert-butyl-£x-phenylnitrone (PBN) resulted in normalization of the several biochemical parameters to those characteristic of the young animals; coincidentally, the short-term memory index was restored to the young animal values. These results provide the first evidence that there is likely a linkage between the age-dependent accumulation of oxidized enzymes and the loss of physiological function.

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2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclos... more 2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclosed. These materials are useful as pharmaceutical agents for oral or parenteral. e.g. intravenous administration to patients su?'ering from acute central nervous system oxidation as occurs in a stroke or from gradual central nervous system oxidation which can exhibit itself as progressive central nervous system function loss. The materials are also used to ameliorate the side elfects of oxidative-damage causing antineoplastic disease treatments.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2001

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Emerging Strategies in Neuroprotection

: NATO needs better methods of measuring and predicting human performance, as well as novel metho... more : NATO needs better methods of measuring and predicting human performance, as well as novel methods of training soldiers that might enhance performance. New breakthroughs with magnetic resonance imaging (MRI) show promise in both areas. Rationale: Our group initially and now at least three others, have demonstrated that a baseline fMRI scan while subjects are performing a task can predict who will respond poorly or well after sleep deprivation (SD). That is, the degree a person activates specific brain regions while performing a task when fully rested is related to and can predict their performance under a stressful condition like sleep deprivation (SD). We discuss whether more research in this area might develop this into a useful vocational screening tool. Description of methods employed and results obtained: Over the past year, we have developed methods to detect brain activity during MRI scanning and to feed those activity levels back to participants during the scan. This real-t...

Toxins

The larvae of the black soldier fly (Hermetia illucens L., BSFL) have received increased industri... more The larvae of the black soldier fly (Hermetia illucens L., BSFL) have received increased industrial interest as a novel protein source for food and feed. Previous research has found that insects, including BSFL, are capable of metabolically converting aflatoxin B1 (AFB1), but recovery of total AFB1 is less than 20% when accounting for its conversion to most known metabolites. The aim of this study was to examine the conversion of AFB1 by S9 extracts of BSFL reared on substrates with or without AFB1. Liver S9 of Aroclor-induced rats was used as a reference. To investigate whether cytochrome P450 enzymes are involved in the conversion of AFB1, the inhibitor piperonyl butoxide (PBO) was tested in a number of treatments. The results showed that approximately 60% of AFB1 was converted to aflatoxicol and aflatoxin P1. The remaining 40% of AFB1 was not converted. Cytochrome P450s were indeed responsible for metabolic conversion of AFB1 into AFP1, and a cytoplasmic reductase was most likely...

Ann N Y Acad Sci, 1998

The free radical theory of aging proposes that reactive oxygen species (ROS) cause oxidative dama... more The free radical theory of aging proposes that reactive oxygen species (ROS) cause oxidative damage over the lifetime of the subject. It is the cumulative and potentially increasing amount of accumulated damage that accounts for the dysfunctions and pathologies seen in normal aging. We have prevously demonstrated that both normal rodent brain aging and normal human brain aging are associated with an increase in oxidative modification of proteins and in changes in plasma membrane lipids. Several lines of investigation indicate that one of the likely sources of ROS is the mitochondria. There is an increase in oxidative damage to the mitochondrial genome in aging and a decreased expression of mitochondrial mRNA in aging. We have used a multidisciplinary approach to the characterization of the changes that occur in aging and in the modeling of brain aging, both in vitro and in vivo. Exposure of rodents to acute normobaric hyperoxia for up to 24 h results in oxidative modifications in cytosolic proteins and loss of activity for the oxidation-sensitve enzymes glutamine synthetase and creatine kinase. Cytoskeletal protein spin labeling also reveals synaptosomal membrane protein oxidation following hyperoxia. These changes are similar to the changes seen in senescent brains, compared to young adult controls. The antioxidant spin-trapping compound N-tert-butyl-=-phenylnitrone (PBN) was effective in preventing all of these changes. In a related study, we characterized the changes in brain protein spin labeling and cytosolic enzyme activity in a series of phenotypically selected senescence-accelerated mice (SAMP), compared to a resistant line (SAMR1) that was derived from the same original parents. In general, the SAM mice demonstrated greater oxidative changes in brain proteins. In a sequel study, a group of mice from the SAMP8-sensitive line were compared to the SAMR1resistant mice following 14 days of daily PBN treatment at a dose of 30mg/kg. PBN treatment resulted in an improvement in the cytoskeletal protein labeling toward that of the normal control line (SAMR1). The results of these and related studies indicate that the changes in brain function seen in several different studies may be related to the progressive oxidation of critical brain proteins and lipids. These coma

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Abstract : NATO needs better methods of measuring and predicting human performance, as well as no... more Abstract : NATO needs better methods of measuring and predicting human performance, as well as novel methods of training soldiers that might enhance performance. New breakthroughs with magnetic resonance imaging (MRI) show promise in both areas. Rationale: Our group initially and now at least three others, have demonstrated that a baseline fMRI scan while subjects are performing a task can predict who will respond poorly or well after sleep deprivation (SD). That is, the degree a person activates specific brain regions while performing a task when fully rested is related to and can predict their performance under a stressful condition like sleep deprivation (SD). We discuss whether more research in this area might develop this into a useful vocational screening tool. Description of methods employed and results obtained: Over the past year, we have developed methods to detect brain activity during MRI scanning and to feed those activity levels back to participants during the scan. This real-time feedback allows participants to adjust their performance based on their own brain activity, with the aim to increase brain activity. We have completed a preliminary study with 12 healthy young adults in a 3 Tesla Siemens MRI scanner and have ongoing research to further optimize brain feedback protocols. In the preliminary study, we first completed a baseline scan where participants were asked to imagine moving their right hand. In the second and third scans, participants were given real or false feedback (counterbalanced order) regarding their brain activity in left premotor brain cortex. Often brain activity decreases with repeated scanning, perhaps due to fatigue effects. We found that brain activity with real feedback remained at baseline levels in left premotor cortex, while brain activity with false feedback decreased. We hypothesize that brain feedback training can be used to enhance performance or maintain performance at baseline levels despite fatigue.

J Mol Neurosci, 1991

Brain is extremely susceptible to oxidative damage. Utilizing a series of novel approaches, we ha... more Brain is extremely susceptible to oxidative damage. Utilizing a series of novel approaches, we have demonstrated that oxidative damage occurs during an ischemia/reperfusion insult (IRI) to brain. Thus, we have demonstrated that an IRI to Mongolian gerbil brain results in: (1) an enhanced rate of salicylate hydroxylation, implicating an increased flux of hydroxyl free radicals; (2) an enhanced flux of free radicals as determined by spin-trapping; (3) an enhanced level of endogenous protein oxidation; (4) a decrease in glutamine synthetase (GS) activity, an enzyme very sensitive to oxidative damage; and (5) demonstration of protection from an IRI by administering the spin-trapping agent alpha-phenyl-tert-butyl nitrone (PBN). The novel observation that PBN offers protection from the lethality brought on by a brain IRI appears to be clearly linked to the ability of the administered spin-trap to inhibit oxidative damage as evidenced by the decreased amount of brain protein oxidation and the prevention of an IRI-mediated loss of GS activity in treated animals. Aged gerbils are more sensitive to the lethal action of a brain IRI than younger animals, but they are protected by PBN administration as are the younger animals. Older gerbils have a significantly higher level of oxidized protein in the brain. Older gerbils have decreased activities of GS and neutral protease, the enzyme that removes oxidized protein, than younger animals. Chronic twice daily administration of PBN (32 mg/kg) for 14 days to older animals significantly lowered brain oxidized protein levels and raised GS and neutral protease activity to those observed in younger animals. Cessation of PBN administration resulted in a time-dependent restoration of protein oxidation levels and enzyme activities back to those observed prior to spin-trap administration. Older gerbils exhibit significantly higher errors in a radial arm maze than younger animals, but older gerbils that had received chronic daily treatments of PBN (32 mg/kg) for 14 days committed significantly less errors than untreated controls. The errors committed in PBN-treated animals was decreased down to the level of those observed in younger animals. Clearly the spin-trapping agent, PBN, appears to have promise in: (1) elucidation of the role of oxidative damage in normal brain function during aging, (2) understanding the development of pathological conditions, and (3) development of treatment regimens for prevention of damage that occurs during the development of pathological conditions and in aging.

Molecular Mechanisms of Dementia, 1997

Alzheimer’s disease (AD) research has progressed greatly since the first description of AD by Alz... more Alzheimer’s disease (AD) research has progressed greatly since the first description of AD by Alzheimer (1) very early in this century. Three pathological hallmarks of AD are: 1. The presence in certain brain regions of senile plaques (SP), entities composed of aggregated β-amyloid surrounded by dystrophic neurites and other moieties; 2. Neurofibrillary tangles (NFT), primarily composed of phosphorylated τ, a cytoskeletal protein, and other moieties; and 3. Loss of synapses (2–4).

2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclos... more 2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclosed. These materials are useful as pharmaceutical agents for oral or parenteral. e.g. intravenous administration to patients su?'ering from acute central nervous system oxidation as occurs in a stroke or from gradual central nervous system oxidation which can exhibit itself as progressive central nervous system function loss. The materials are also used to ameliorate the side elfects of oxidative-damage causing antineoplastic disease treatments.

Pharmacology Biochemistry and Behavior, 1976

Variable interval responding maintained by intravenous codeine and ethanol injections in the rhes... more Variable interval responding maintained by intravenous codeine and ethanol injections in the rhesus monkey. PHARMAC. BIOCHEM. BEHAV. 5(5) 577-582, 1976.-Rhesus monkeys were trained to respond under a variable interval 2 min schedule for codeine or ethanol injections. Both codeine and ethanol were effective in the initiation of variable-interval responding; responding was maintained over a range of codeine (0.003-1.0 mg/kg/injection) and ethanol doses (32.0-560 mg/kg/injeetion). Maximum rates of responding were obtained at the 0.01 mg/kg/injection codeine dose (0.14 responses/see) and at the 180 mg/kg/injection codeine dose (0.19 responses/sec). Rates of responsing were bitonic functions of the reinforcer dose for both codeine and ethanol; maximum rates were obtained at intermediate doses and lower rates occurred at the extremes of the dose range. Both codeine and ethanol showed within-session decreases in responding across the range of reinforcer doses. Codeine-reinforced responding declined in rate within the one-hour session without a similar change in the frequency of drug injection; in contrast, both ethanol-reinforced responding and the frequency of ethanol injections declined within each session across a range of doses. Increasing or decreasing the codeine dose halfway through the one-hour session resulted in increases or decreases in codeine responding compared to controls. These data indicate that the progressive decline in codeine-reinforced responding is not the result of a generalized disruption of responding.

Free Radicals and Aging, 1992

During aging a number of enzymes accumulate as catalytically inactive or less active forms. The a... more During aging a number of enzymes accumulate as catalytically inactive or less active forms. The age-related changes in catalytic activity are due in part to reactions of the protein with "active" oxygen species such as ozone, singlet oxygen, or with oxygen free radicals as are produced during exposure to ionizing radiation or to metal ion catalyzed oxidation (MCO) systems. The levels of oxidized proteins in cultured human fibroblasts from individuals of various ages and in liver and brain extracts of rats of different ages increase progressively with age, and in old rats can represent 30-50% of the total cellular protein. The age-related increase in oxidized protein in rat liver and brain tissue is accompanied by a loss of glutamine synthetase (OS) and glucose-6-P dehydrogenase (0-6-PDH) activities, and to a decrease in the level of cytosolic neutral protease activity which is responsible for the degradation of oxidized (denatured) protein. Of particular significance are the results of experiments showing that similar age-related changes occur in the gerbil brain and that these changes are accompanied by a loss of short-term memory as measured by the radial arm maze technique. Chronic treatment (intraperitoneal injections) of old animals with the free ~adical spin-trap reagent, N-tert-butyl-£x-phenylnitrone (PBN) resulted in normalization of the several biochemical parameters to those characteristic of the young animals; coincidentally, the short-term memory index was restored to the young animal values. These results provide the first evidence that there is likely a linkage between the age-dependent accumulation of oxidized enzymes and the loss of physiological function.

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2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclos... more 2.4-disulfonyl ot-phenyl-tert-butyl nitrone and its pharmaceutically acceptable salts are disclosed. These materials are useful as pharmaceutical agents for oral or parenteral. e.g. intravenous administration to patients su?'ering from acute central nervous system oxidation as occurs in a stroke or from gradual central nervous system oxidation which can exhibit itself as progressive central nervous system function loss. The materials are also used to ameliorate the side elfects of oxidative-damage causing antineoplastic disease treatments.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2001

Click here to let us know how access to this document benefits you.

Emerging Strategies in Neuroprotection

: NATO needs better methods of measuring and predicting human performance, as well as novel metho... more : NATO needs better methods of measuring and predicting human performance, as well as novel methods of training soldiers that might enhance performance. New breakthroughs with magnetic resonance imaging (MRI) show promise in both areas. Rationale: Our group initially and now at least three others, have demonstrated that a baseline fMRI scan while subjects are performing a task can predict who will respond poorly or well after sleep deprivation (SD). That is, the degree a person activates specific brain regions while performing a task when fully rested is related to and can predict their performance under a stressful condition like sleep deprivation (SD). We discuss whether more research in this area might develop this into a useful vocational screening tool. Description of methods employed and results obtained: Over the past year, we have developed methods to detect brain activity during MRI scanning and to feed those activity levels back to participants during the scan. This real-t...

Toxins

The larvae of the black soldier fly (Hermetia illucens L., BSFL) have received increased industri... more The larvae of the black soldier fly (Hermetia illucens L., BSFL) have received increased industrial interest as a novel protein source for food and feed. Previous research has found that insects, including BSFL, are capable of metabolically converting aflatoxin B1 (AFB1), but recovery of total AFB1 is less than 20% when accounting for its conversion to most known metabolites. The aim of this study was to examine the conversion of AFB1 by S9 extracts of BSFL reared on substrates with or without AFB1. Liver S9 of Aroclor-induced rats was used as a reference. To investigate whether cytochrome P450 enzymes are involved in the conversion of AFB1, the inhibitor piperonyl butoxide (PBO) was tested in a number of treatments. The results showed that approximately 60% of AFB1 was converted to aflatoxicol and aflatoxin P1. The remaining 40% of AFB1 was not converted. Cytochrome P450s were indeed responsible for metabolic conversion of AFB1 into AFP1, and a cytoplasmic reductase was most likely...

Ann N Y Acad Sci, 1998

The free radical theory of aging proposes that reactive oxygen species (ROS) cause oxidative dama... more The free radical theory of aging proposes that reactive oxygen species (ROS) cause oxidative damage over the lifetime of the subject. It is the cumulative and potentially increasing amount of accumulated damage that accounts for the dysfunctions and pathologies seen in normal aging. We have prevously demonstrated that both normal rodent brain aging and normal human brain aging are associated with an increase in oxidative modification of proteins and in changes in plasma membrane lipids. Several lines of investigation indicate that one of the likely sources of ROS is the mitochondria. There is an increase in oxidative damage to the mitochondrial genome in aging and a decreased expression of mitochondrial mRNA in aging. We have used a multidisciplinary approach to the characterization of the changes that occur in aging and in the modeling of brain aging, both in vitro and in vivo. Exposure of rodents to acute normobaric hyperoxia for up to 24 h results in oxidative modifications in cytosolic proteins and loss of activity for the oxidation-sensitve enzymes glutamine synthetase and creatine kinase. Cytoskeletal protein spin labeling also reveals synaptosomal membrane protein oxidation following hyperoxia. These changes are similar to the changes seen in senescent brains, compared to young adult controls. The antioxidant spin-trapping compound N-tert-butyl-=-phenylnitrone (PBN) was effective in preventing all of these changes. In a related study, we characterized the changes in brain protein spin labeling and cytosolic enzyme activity in a series of phenotypically selected senescence-accelerated mice (SAMP), compared to a resistant line (SAMR1) that was derived from the same original parents. In general, the SAM mice demonstrated greater oxidative changes in brain proteins. In a sequel study, a group of mice from the SAMP8-sensitive line were compared to the SAMR1resistant mice following 14 days of daily PBN treatment at a dose of 30mg/kg. PBN treatment resulted in an improvement in the cytoskeletal protein labeling toward that of the normal control line (SAMR1). The results of these and related studies indicate that the changes in brain function seen in several different studies may be related to the progressive oxidation of critical brain proteins and lipids. These coma

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Abstract : NATO needs better methods of measuring and predicting human performance, as well as no... more Abstract : NATO needs better methods of measuring and predicting human performance, as well as novel methods of training soldiers that might enhance performance. New breakthroughs with magnetic resonance imaging (MRI) show promise in both areas. Rationale: Our group initially and now at least three others, have demonstrated that a baseline fMRI scan while subjects are performing a task can predict who will respond poorly or well after sleep deprivation (SD). That is, the degree a person activates specific brain regions while performing a task when fully rested is related to and can predict their performance under a stressful condition like sleep deprivation (SD). We discuss whether more research in this area might develop this into a useful vocational screening tool. Description of methods employed and results obtained: Over the past year, we have developed methods to detect brain activity during MRI scanning and to feed those activity levels back to participants during the scan. This real-time feedback allows participants to adjust their performance based on their own brain activity, with the aim to increase brain activity. We have completed a preliminary study with 12 healthy young adults in a 3 Tesla Siemens MRI scanner and have ongoing research to further optimize brain feedback protocols. In the preliminary study, we first completed a baseline scan where participants were asked to imagine moving their right hand. In the second and third scans, participants were given real or false feedback (counterbalanced order) regarding their brain activity in left premotor brain cortex. Often brain activity decreases with repeated scanning, perhaps due to fatigue effects. We found that brain activity with real feedback remained at baseline levels in left premotor cortex, while brain activity with false feedback decreased. We hypothesize that brain feedback training can be used to enhance performance or maintain performance at baseline levels despite fatigue.

J Mol Neurosci, 1991

Brain is extremely susceptible to oxidative damage. Utilizing a series of novel approaches, we ha... more Brain is extremely susceptible to oxidative damage. Utilizing a series of novel approaches, we have demonstrated that oxidative damage occurs during an ischemia/reperfusion insult (IRI) to brain. Thus, we have demonstrated that an IRI to Mongolian gerbil brain results in: (1) an enhanced rate of salicylate hydroxylation, implicating an increased flux of hydroxyl free radicals; (2) an enhanced flux of free radicals as determined by spin-trapping; (3) an enhanced level of endogenous protein oxidation; (4) a decrease in glutamine synthetase (GS) activity, an enzyme very sensitive to oxidative damage; and (5) demonstration of protection from an IRI by administering the spin-trapping agent alpha-phenyl-tert-butyl nitrone (PBN). The novel observation that PBN offers protection from the lethality brought on by a brain IRI appears to be clearly linked to the ability of the administered spin-trap to inhibit oxidative damage as evidenced by the decreased amount of brain protein oxidation and the prevention of an IRI-mediated loss of GS activity in treated animals. Aged gerbils are more sensitive to the lethal action of a brain IRI than younger animals, but they are protected by PBN administration as are the younger animals. Older gerbils have a significantly higher level of oxidized protein in the brain. Older gerbils have decreased activities of GS and neutral protease, the enzyme that removes oxidized protein, than younger animals. Chronic twice daily administration of PBN (32 mg/kg) for 14 days to older animals significantly lowered brain oxidized protein levels and raised GS and neutral protease activity to those observed in younger animals. Cessation of PBN administration resulted in a time-dependent restoration of protein oxidation levels and enzyme activities back to those observed prior to spin-trap administration. Older gerbils exhibit significantly higher errors in a radial arm maze than younger animals, but older gerbils that had received chronic daily treatments of PBN (32 mg/kg) for 14 days committed significantly less errors than untreated controls. The errors committed in PBN-treated animals was decreased down to the level of those observed in younger animals. Clearly the spin-trapping agent, PBN, appears to have promise in: (1) elucidation of the role of oxidative damage in normal brain function during aging, (2) understanding the development of pathological conditions, and (3) development of treatment regimens for prevention of damage that occurs during the development of pathological conditions and in aging.

Molecular Mechanisms of Dementia, 1997

Alzheimer’s disease (AD) research has progressed greatly since the first description of AD by Alz... more Alzheimer’s disease (AD) research has progressed greatly since the first description of AD by Alzheimer (1) very early in this century. Three pathological hallmarks of AD are: 1. The presence in certain brain regions of senile plaques (SP), entities composed of aggregated β-amyloid surrounded by dystrophic neurites and other moieties; 2. Neurofibrillary tangles (NFT), primarily composed of phosphorylated τ, a cytoskeletal protein, and other moieties; and 3. Loss of synapses (2–4).