Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer9s disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down9s syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients9 brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

https://www.embopress.org/doi/pdf/10.15252/emmm.201606210

The amyloid hypothesis of Alzheimer's disease at 25 years

Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

/pdf/clearance-systems-in-the-brain-implications-for-alzheimer-5ed0fh7q5o.pdf

Clearance systems in the brain—implications for Alzheimer disease

The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of t...

/pdf/blood-brain-barrier-from-physiology-to-disease-and-back-1xwjgb63cg.pdf

Blood-Brain Barrier: From Physiology to Disease and Back

The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer's and Parkinson's diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer's disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson's disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer's and Parkinson's diseases, from where it spreads to other areas.

http://science.sciencemag.org/content/sci/349/6248/1255555.full.pdf

Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein

Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid-β (Aβ) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleep-wake cycle directly influences levels of Aβ in the brain. In experimental models, sleep deprivation increases the concentration of soluble Aβ and results in chronic accumulation of Aβ, whereas sleep extension has the opposite effect. Furthermore, once Aβ accumulates, increased wakefulness and altered sleep patterns develop. Individuals with early Aβ deposition who still have normal cognitive function report sleep abnormalities, as do individuals with very mild dementia due to AD. Thus, sleep and neurodegenerative disease may influence each other in many ways that have important implications for the diagnosis and treatment of AD.

Sleep and Alzheimer disease pathology--a bidirectional relationship.

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.

https://jamanetwork.com/journals/jamaneurology/articlepdf/1108053/noc110054_51_58.pdf

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

Alzheimer’s disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-b (Ab) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Ab42 compared to Ab40 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 Ab 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 Ab42 to Ab40 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 Ab42 relative to Ab40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Ab42 into plaques, leading to reduced recovery of Ab42 in cerebrospinal fluid (CSF). Reversible exchange of Ab42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Ab42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Ab42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Ab42 concentrations in the CSF.

/pdf/increased-in-vivo-amyloid-b42-production-exchange-and-loss-4e0k1a4jx2.pdf

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

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.

https://jamanetwork.com/journals/jamaneurology/articlepdf/1475602/noc120063_1591_1597.pdf

Rachel Potter

Papers

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

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

β-Amyloid Dynamics in Human Plasma