Tom Kasten

Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Decreased clearance of CNS beta-amyloid in Alzheimer's disease.

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology

Decreased sleep and attenuation of circadian fluctuations in Aβ reflect amyloid-associated pathology in Alzheimer’s disease. Don’t Let Amyloid Keep You Awake at Night The accumulation in the brain of the neurotoxic β-amyloid (Aβ) peptide is a key event in the pathogenesis of Alzheimer’s disease (AD). Aβ accumulation in amyloid plaques begins about 10 to 15 years before cognitive decline and is already very substantial by the time memory and thinking problems begin. It is critical to determine whether there are functional and biochemical changes in the brain that are present when Aβ is accumulating but before the appearance of dementia to initiate therapy earlier as well as to assess the therapeutic effects of new drugs. Previous work has shown that soluble forms of Aβ fluctuate in the brain with the sleep-wake cycle. Now, Roh and colleagues show that diurnal fluctuation of Aβ occurs in different brain regions in young adult mice that develop accumulation of Aβ. However, Aβ fluctuation disappeared with the onset of amyloid plaque deposition, most likely due to insoluble Aβ plaques sequestering soluble forms of Aβ. Similar findings were seen in the cerebrospinal fluid of humans with genetic mutations that cause early-onset, autosomal dominant AD. Coincident with increasing Aβ accumulation, the researchers found that the amount of time mice were awake when they were supposed to be asleep increased by 50%. Actively immunizing mice with Aβ prevented amyloid plaque formation, as well as maintaining normal circadian Aβ fluctuation and normal sleep patterns. These findings suggest that changes in the sleep-wake cycle may be caused by Aβ accumulation. If analogous abnormalities in the sleep-wake cycle are present in cognitively normal and very mildly impaired humans who are developing AD pathology, the sleep-wake cycle may be a useful indicator of early brain dysfunction that could be assessed as an outcome measure in response to therapeutic interventions. Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer’s disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ42 normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system may be functional and biochemical indicators, respectively, of Aβ-associated pathology.

Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System

BACKGROUND The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). OBJECTIVE To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. DESIGN Repeated-measures case-control study. SETTING Washington University School of Medicine in St Louis, Missouri. PARTICIPANTS Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. MAIN OUTCOME MEASURES In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. RESULTS Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. CONCLUSIONS A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

Increased in Vivo Amyloid-β42 Production, Exchange, and Loss in Presenilin Mutation Carriers

Aβ42 kinetics are altered in the central nervous system of patients with autosomal dominant Alzheimer’s disease. Aβ42: A Cycle of Gain and Loss The amyloid hypothesis of Alzheimer’s disease (AD) proposes that increased production or impaired clearance of Aβ42 peptide causes deposition of amyloid in plaques, nerve destruction, and ultimately AD dementia. Animal model studies based on human autosomal dominant mutations have shown that increasing the production of Aβ peptides, especially Aβ42, can recapitulate amyloidosis. Potter et al. have now used a stable isotope labeling kinetics (SILK) approach to measure Aβ isoform kinetics to test specific hypotheses regarding the production rates of the Aβ38, Aβ40, and Aβ42 peptides in individuals carrying autosomal dominant AD mutations and related noncarriers. The authors found an increased Aβ42 production rate in AD mutation carriers that was ~25% higher than that in noncarriers. In addition to increased production rates, the authors unexpectedly found altered Aβ42 kinetics in mutation carriers that indicated both a reversible exchange pool and increased irreversible loss. Future studies could quantify the effects of proposed disease-modifying drugs to normalize altered Aβ kinetics and provide a metric to gauge target engagement for therapeutic trials. Alzheimer’s disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques, leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.

Decreased Clearance of CNS Amyloid-β in Alzheimer’s Disease

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Amyloid-β efflux from the central nervous system into the plasma.

The aim of this study was to measure the flux of amyloid‐β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS).

Age and amyloid effects on human central nervous system amyloid-beta kinetics.

Age is the single greatest risk factor for Alzheimers disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid‐beta (Aβ) kinetics in the central nervous system (CNS) of humans.

β-Amyloid Dynamics in Human Plasma

OBJECTIVES To investigate dynamic changes in human plasma β-amyloid (Aβ) concentrations, evaluate the effects of aging and amyloidosis on these dynamics, and determine their correlation with cerebrospinal fluid (CSF) Aβ concentrations. DESIGN A repeated plasma and CSF sampling study. SETTING The Washington University School of Medicine in St Louis, Missouri. PARTICIPANTS Older adults with amyloid deposition (Amyloid+), age-matched controls without amyloid deposition (Amyloid-), and younger normal controls (YNCs) were enrolled for the study. MAIN OUTCOME MEASURES Hourly measurements of plasma Aβ were compared between groups by age and amyloidosis. Plasma Aβ and CSF Aβ concentrations were compared for correlation, linear increase, and circadian patterns. RESULTS Circadian patterns were observed in plasma Aβ, with diminished amplitudes with aging. Linear increase of Aβ was only observed for CSF Aβ in the YNC and Amyloid- groups, but not in the Amyloid+ group. No linear increase was observed for plasma Aβ. No significant correlations were found between plasma and CSF Aβ concentrations. CONCLUSIONS Plasma Aβ, like CSF, demonstrates a circadian pattern that is reduced in amplitude with increasing age but is unaffected by amyloid deposition. However, we found no evidence that plasma and CSF Aβ concentrations were related on an hourly or individual basis.

Diurnal Patterns of Soluble Amyloid Precursor Protein Metabolites in the Human Central Nervous System

The amyloid-β (Aβ) protein is diurnally regulated in both the cerebrospinal fluid and blood in healthy adults; circadian amplitudes decrease with aging and the presence of cerebral Aβ deposits. The cause of the Aβ diurnal pattern is poorly understood. One hypothesis is that the Amyloid Precursor Protein (APP) is diurnally regulated, leading to APP product diurnal patterns. APP in the central nervous system is processed either via the β-pathway (amyloidogenic), generating soluble APP-β (sAPPβ) and Aβ, or the α-pathway (non-amyloidogenic), releasing soluble APP-α (sAPPα). To elucidate the potential contributions of APP to the Aβ diurnal pattern and the balance of the α- and β- pathways in APP processing, we measured APP proteolytic products over 36 hours in human cerebrospinal fluid from cognitively normal and Alzheimers disease participants. We found diurnal patterns in sAPPα, sAPPβ, Aβ40, and Aβ42, which diminish with increased age, that support the hypothesis that APP is diurnally regulated in the human central nervous system and thus results in Aβ diurnal patterns. We also found that the four APP metabolites were positively correlated in all participants without cerebral Aβ deposits. This positive correlation suggests that the α- and β- APP pathways are non-competitive under normal physiologic conditions where APP availability may be the limiting factor that determines sAPPα and sAPPβ production. However, in participants with cerebral Aβ deposits, there was no correlation of Aβ to sAPP metabolites, suggesting that normal physiologic regulation of cerebrospinal fluid Aβ is impaired in the presence of amyloidosis. Lastly, we found that the ratio of sAPPβ to sAPPα was significantly higher in participants with cerebral Aβ deposits versus those without deposits. Therefore, the sAPPβ to sAPPα ratio may be a useful biomarker for cerebral amyloidosis.