Altered γ‐secretase activity in mild cognitive impairment and Alzheimer's disease

Kakuda, Nobuto; Shoji, Mikio; Arai, Hiroyuki; Furukawa, Koichi; Ikeuchi, Takeshi; Akazawa, Kohei; Takami, Mako; Hatsuta, Hiroyuki; Murayama, Shigeo; Hashimoto, Yasuhiro; Miyajima, Masakazu; Arai, Hajime; Nagashima, Yu; Yamaguchi, Hideyo; Kuwano, Ryozo; Nagaike, Kazuhiro; Ihara, Yasuo

doi:10.1002/emmm.201200214

Cited by 61 publications

(66 citation statements)

References 31 publications

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“…Subsequently, they demonstrated that Aβ43 was abundant in vivo , exhibited a greater propensity to aggregate, provoked Aβ42 polymerization, and was more neurotoxic than Aβ42. Recently, Aβ43 was identified and quantified in CSF from human AD/mild cognitive impairment (MCI) patients and control subjects using a commercial Aβ43 enzyme-linked immunosorbent assay (ELISA) [37]. Concentrations in CSF of both Aβ42 and Aβ43 were significantly lower in the patients compared with control subjects indicating an accumulation of these peptides in the brain.…”

Section: Introductionmentioning

confidence: 99%

The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease

et al. 2013

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The amyloid-cascade hypothesis posits that the role of amyloid β-peptide (Aβ) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of Aβ are produced, of which the 40 and 42 residue variants (Aβ40 and Aβ42) are the most common. Aβ42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer Aβ isoforms, like the less studied Aβ43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate Aβ43 in AD, we conducted a quantitative study on Aβ43 levels in human brain. We homogenized human brain tissue and prepared fractions of various solubility; tris buffered saline (TBS), sodium dodecyl sulfate (SDS) and formic acid (FA). Levels of Aβ43, as well as Aβ40 and Aβ42, were quantified using ELISA. We compared quantitative data showing Aβ levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed Aβ43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases. Aβ42 and Aβ43 were enriched in the less soluble fractions (SDS and FA) of SAD and FAD cases in both occipital and frontal cortex. Thus, although the total levels of Aβ43 in human brain are low compared to Aβ40 and Aβ42, we suggest that Aβ43 could initiate the formation of oligomers and amyloid plaques and thereby be crucial to AD pathogenesis.

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Section: Introductionmentioning

confidence: 99%

The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease

et al. 2013

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“…For all brains registered at the bank, written informed consent for their use for medical research was obtained from the patient prior to death or from the patient's family. Brain specimens were collected from Broadmann area 22 (superior temporal gyrus) for 12 AD patients (79.2±4.4 years of age) and 13 control patients (80.4±4.2 years of age) [48]. Detailed descriptions of all subjects, including the relative protein/tubulin ratio for each individual, are shown in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Aβ generation in Alzheimer’s disease

Saito

Inoue

Zhu

et al. 2012

Mol Neurodegeneration

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BackgroundOne of the best-characterized causative factors of Alzheimer’s disease (AD) is the generation of amyloid-β peptide (Aβ). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances Aβ generation. However, the molecular linkage between epileptic seizures and Aβ generation in AD remains unclear.ResultsX11 and X11-like (X11L) gene knockout mice suffered from epileptic seizures, along with a malfunction of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Genetic ablation of HCN1 in mice and HCN1 channel blockage in cultured Neuro2a (N2a) cells enhanced Aβ generation. Interestingly, HCN1 levels dramatically decreased in the temporal lobe of cynomolgus monkeys (Macaca fascicularis) during aging and were significantly diminished in the temporal lobe of sporadic AD patients.ConclusionBecause HCN1 associates with amyloid-β precursor protein (APP) and X11/X11L in the brain, genetic deficiency of X11/X11L may induce aberrant HCN1 distribution along with epilepsy. Moreover, the reduction in HCN1 levels in aged primates may contribute to augmented Aβ generation. Taken together, HCN1 is proposed to play an important role in the molecular linkage between epileptic seizures and Aβ generation, and in the aggravation of sporadic AD.

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“…Western blot analysis in our study confirmed that higher levels of PSEN1 in overweight and obese adolescents were due to raised circulating levels of the fulllength protein (Fig 3), but the clinical meaning of this observation is not clear and deserves further studies. Concentrations of PSEN1 have been measured in cerebrospinal fluid 51 and brains from patients with dementia and AD, with inconsistent results. [52][53][54] Phosphorylation of PSEN1 seems to increase the profibrillogenic Ab42/40 ratio and it has been found enhanced in AD brains.…”

Section: Figurementioning

confidence: 99%

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

Luciano¹,

Barraco²,

Muraca³

et al. 2015

PEDIATRICS

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OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid b-protein 42 (Ab42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI.METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent b-cell function (HOMA-b) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS:Obese adolescents had values of Ab42 higher than overweight and normal-weight peers (190.2 6 9.16 vs 125.9 6 7.38 vs 129.5 6 7.65 pg/mL; P , .0001) as well as higher levels of PSEN1 (2.34 6 0.20 vs 1.95 6 0.20 vs 1.65 6 0.26 ng/mL; P , .0001). Concentrations of Ab42 were significantly correlated with BMI (r = 0.262; P , .0001), HOMA-IR (r = 0.261; P , .0001) and QUICKI (r = 20.220; P , .0001). PSEN1 levels were correlated with BMI (r = 0.248; P , .0001), HOMA-IR (r = 0.242; P , .0001), and QUICKI (r = 20.256; P , .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein.CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD. WHAT'S KNOWN ON THIS SUBJECT:Insulin resistance plays a role in obesity. Recently it has been associated with increased risk of AD. Ab42 and PSEN1 are molecules associated with increased risk of later AD. Patients affected by AD show elevated levels of plasma Ab42.WHAT THIS STUDY ADDS: Levels of Ab42 and PSEN1 are significantly elevated in obese adolescents and correlated with the degree of both adiposity and systemic insulin resistance. Dr Manco conceptualized and designed the study, performed assays, analyzed data and interpreted results, contributed to the discussion, and critically revised the manuscript; Ms Luciano and Ms Barraco conceptualized and designed the study, performed assays, analyzed data and interpreted results, and drafted the manuscript; Drs Muraca, Ottino, Sforza, Rustico, and Morino and Ms Spreghini enrolled patients, collected growth data, and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This condition has been termed as "brain insulin resistance" and seems to be a constant trait that precedes clinical symptoms of dementia and AD even for decades. Researchers refer to AD also as "type 3 diabetes" by virtue of the analogous brain glucose hypometabolism that characterizes both conditions and the high rate of their co-occurrence. 1,4,5 Patients with T2D exhibit an increased risk of developing cognitive impairment and dementia and, vice versa, impaired fasting glucose and diabetes are highly prevalent among patients...

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Altered γ‐secretase activity in mild cognitive impairment and Alzheimer's disease

Cited by 61 publications

References 31 publications

The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease

The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease

Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Aβ generation in Alzheimer’s disease

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

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