Concentrations of amyloid-β protein in cerebrospinal fluid increase with age in patients free from neurodegenerative disease

doi:10.1016/0304-3940(94)90677-7

Neuroscience Letters

Volume 172, Issues 1–2, 19 May 1994, Pages 122-124

https://doi.org/10.1016/0304-3940(94)90677-7 Get rights and content

Abstract

Cerebral deposition of amyloid-β protein (Aβ) is central to the pathogenesis of Alzheimer's disease (AD). Increasing age is one of the few definitively established risk factors for this disease. The concentration of Aβ was measured in cerebrospinal fluid (CSF) with a sensitive enzyme-linked immunosorbent assay in 18 adult neurological patients free from neurodegenerative disease. CSF Aβ increased with age, yielding a significant correlation of 0.84. This observation suggests that increased levels of Aβ in CSF may be an index of age-related changes in the processing of the amyloid-β precursor protein resulting in an increased risk for AD.

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Cited by (47)

Comparison between amyloid-PET and CSF amyloid-β biomarkers in a clinical cohort with memory deficits
2019, Clinica Chimica Acta
Citation Excerpt :
Results of age-dependent changes of Aβ42 concentrations in CSF are somewhat controversial. Several studies reported a linear decrease of CSF Aβ42 with age [44–46] while other studies showed no changes or an increase of Aβ42 [47–50]. However, several factors that might influence Aβ42 findings in CSF have to be taken into account that might explain those diametrical findings as sleep cycle and handling and storage of samples [51,52].
With increasing prevalence of Alzheimer's disease (AD) and advances in research of therapeutic approaches, an early and accurate in-vivo diagnosis is crucial. Different biomarkers that are able to identify AD are currently in focus. However, whether and to which extend results of cerebrospinal fluid (CSF) and imaging biomarkers are comparable, is unclear. This study aims to correlate CSF and amyloid imaging biomarkers comparing them to cognitive measurements in order to determine whether these methods provide identical or complementary information.
The study comprises 33 consecutive patients with suspected cognitive decline that underwent lumbar puncture for CSF biomarker analysis and Amyloid-PET/CT within the diagnostic evaluation of memory impairment. Amyloid PET/CTs were evaluated visually and quantitatively. CSF and imaging data were retrospectively evaluated and results were compared to cognition tests, age, gender, and ApoE status.
Global cortex SUVr levels correlated highly with CSF Aβ_42/40 and moderately with Aβ₄₂ but not with Aβ₄₀. Global cortex SUVr and Aβ_42/40 correlated with mini mental status examination.
This study indicates that Amyloid-PET and CSF biomarkers might not reflect identical clinical information and a combination of both seems to be the most accurate way to characterize clinically unclear cognitive decline.
Mechanisms of protein misfolding: Novel therapeutic approaches to protein-misfolding diseases
2016, Journal of Molecular Structure
Citation Excerpt :
Similarly, the high concentration of Aβ peptide may as well affects AD. This was demonstrated by recent study that showed elevated levels of Aβ in CSF, which may be an index of age-related changes in the processing of the amyloid precursor protein leading to a high risk for AD [42]. Dominant negative mutations are important origins of protein misfolding thereby leading to conformational diseases.
In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially misfolded intermediates aggregate via the interaction with the complementary intermediates and consequently enhance oligomers formation that grows into fibrils and proto-fibrils. The amyloid fibrils for example, accumulate in the brain and central nervous system (CNS) as amyloid deposits in the Parkinson’s disease (PD), Alzheimer’s disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other neurodegenerative diseases. Treatment of such misfolding maladies is considered as one of the most important challenges of the 21st century. Currently, several treatments strategies have been and are being discovered. These therapeutic interventions partly reversed or prevented the pathological state. More recently, a new approach was discovered, which employs nanobodies that targets multisteps in fibril formation pathway that may possibly completely cure these misfolding diseases. Keeping the above views in mind in the current review, we have comprehensively discussed the different mechanisms underlying protein misfolding thereby leading to diseases conditions and their therapeutic interventions.
Reduced expression of pain mediators and pain sensitivity in amyloid precursor protein over-expressing CRND8 transgenic mice
2013, Neuroscience
Citation Excerpt :
Aβ peptides are well known to be the main component of deposits on plaques and tangles found in the brains of patients with Alzheimer’s disease (AD) and are thus involved in the pathogenesis of this disease (Roher et al., 1993). High levels of Aβ peptides were also detected in the cerebrospinal fluid of normal elderly subjects in addition to AD patients (van Gool et al., 1994). It has been shown that APP and its cleaved product Aβ peptides were expressed in small-sized dorsal root ganglion (DRG) neurons in rodents (Kawarabayashi et al., 1991; Sisodia et al., 1993) and humans (Naves et al., 1994), and involved in the survival and axonal growth of DRG neurons during development (Nishimura et al., 2003).
β-Amyloid (Aβ) peptides are derived from the sequential cleavage of the amyloid precursor protein (APP). They are enriched in plaques present in Alzheimer’s brains and thus play important roles in the pathogenesis of this disease. APP is also known to be expressed in the neurons of dorsal root ganglion (DRG) and contributes to neuronal survival and axonal growth during development. However, whether APP and Aβ peptides are involved in nociception and pathological pain states is mostly unknown. In the present study, we have used behavioral, biochemical and morphological approaches to address this issue in both adult rats and APP over-expressing CRND8 transgenic mice. We observed that the Aβ peptide (17–24) was predominantly expressed in small-sized DRG neurons of rats. Following intraplantar (i.pl.) injection of complete Freud’s adjuvant (CFA), the levels of APP and Aβ peptides were significantly reduced in the ipsilateral lumbar 4–6 rat DRG. In 3-, 12- and 24-month-old CRND8 mice, pain sensitivity in response to heat and mechanical stimulation was significantly dampened compared to their age-matched wild-type littermates. In parallel with reduced pain sensitivity, the expression of pain mediators such as substance P, calcitonin gene-related peptide and transient receptor potential vanilloid-1 was significantly reduced in L4–6 DRG of CRND8 mice. Although i.pl. injection of CFA induced a rather similar pattern of inflammatory pain in 3-month-old CRND8 mice and their wild-type littermates, recovery from inflammatory pain seemed faster in 12-month-old CRND8 mice than wild-type mice. These findings suggest that APP and Aβ peptides suppress both nociception and inflammatory pain and are likely involved in blunt pain perception of Alzheimer’s patients in clinical settings.
Large quantities of Aβ peptide are constitutively released during amyloid precursor protein metabolism in vivo and in vitro
2011, Journal of Biological Chemistry
Citation Excerpt :
Alternatively, cleavage of APP by α-secretase occurs within the Aβ domain, precluding the formation of Aβ and resulting in the secretion of sAPPα, a short peptide called p3, and a C-terminal domain, none of which are amyloidogenic. Both in vitro and in vivo evidence suggests that Aβ is secreted from cells under normal physiological conditions (3, 4, 7–9) but the absolute amount, an important consideration given its proposed roles and pharmacologic interest, has not been precisely calculated. In addition, the relative amount of intracellular versus extracellular Aβ production and its ultimate disposition in neurons is unclear (10).
The metabolism of the amyloid precursor protein (APP) has been extensively investigated because its processing generates the amyloid-β-peptide (Aβ), which is a likely cause of Alzheimer disease. Much prior research has focused on APP processing using transgenic constructs and heterologous cell lines. Work to date in native neuronal cultures suggests that Aβ is produced in very large amounts. We sought to investigate APP metabolism and Aβ production simultaneously under more physiological conditions in vivo and in vitro using cultured rat cortical neurons and live pigs. We found in cultured neurons that both APP and Aβ are secreted rapidly and at extremely high rates into the extracellular space (2–4 molecules/neuron/s for Aβ). Little APP is degraded outside of the pathway that leads to extracellular release. Two metabolic pools of APP are identified, one that is metabolized extremely rapidly (t_½ = 2.2 h), and another, surface pool, composed of both synaptic and extrasynaptic elements, that turns over very slowly. Aβ release and accumulation in the extracellular medium can be accounted for stoichiometrically by the extracellular release of β-cleaved forms of the APP ectodomain. Two α-cleavages of APP occur for every β-cleavage. Consistent with the results seen in cultured neurons, an extremely high rate of Aβ production and secretion from the brain was seen in juvenile pigs. In summary, our experiments show an enormous and rapid production and extracellular release of Aβ and the soluble APP ectodomain. A small, slowly metabolized, surface pool of full-length APP is also identified.
CSF biomarker levels in early and late onset Alzheimer's disease
2009, Neurobiology of Aging
Citation Excerpt :
This overlap stresses the need for clinical follow-up of controls in future studies on common neurodegenerative diseases. Former studies describing CSF biomarker levels in healthy individuals found conflicting results (Green et al., 1999; Sjogren et al., 2001; van Gool et al., 1994). In a study with 231 healthy individuals, Sjogren et al. (2001) found CSF tau but not Aβ1–42 to be age dependent.
To compare CSF levels of beta-amyloid 1–42 (Aβ_1–42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age.
248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (≥65 years) group.
All three biomarkers showed main effects of diagnosis (p < 0.001). There was an interaction between diagnosis and age for all three biomarkers (p < 0.05), as old controls had lower Aβ_1–42 and higher (p)tau than young controls (Aβ_1–42 699 ± 250 versus 866 ± 191 pg/ml, tau 408 ± 245 versus 243 ± 102 pg/ml, ptau-181 60 ± 28 versus 42 ± 15 pg/ml), but there was no difference according to age among AD patients (Aβ_1–42 451 ± 178 versus 425 ± 146 pg/ml, tau 741 ± 460 versus 798 ± 467 pg/ml, ptau-181 91 ± 42 versus 91 ± 41 pg/ml).
We found that the older control group had lower Aβ_1–42 and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.
Site-specific effects of peptide lipidation on β-amyloid aggregation and cytotoxicity
2007, Journal of Biological Chemistry
β-Amyloid (Aβ) aggregates at low concentrations in vivo, and this may involve covalently modified forms of these peptides. Modification of Aβ by 4-hydroxynonenal (4-HNE) initially increases the hydrophobicity of these peptides and subsequently leads to additional reactions, such as peptide cross-linking. To model these initial events, without confounding effects of subsequent reactions, we modified Aβ at each of its amino groups using a chemically simpler, close analogue of 4-HNE, the octanoyl group: K16-octanoic acid (OA)-Aβ, K28-OA-Aβ, and Nα-OA-Aβ. Octanoylation of these sites on Aβ-(1–40) had strikingly different effects on fibril formation. K16-OA-Aβ and K28-OA-Aβ, but not Nα-OA-Aβ, had increased propensity to aggregate. The type of aggregate (electron microscopic appearance) differed with the site of modification. The ability of octanoyl-Aβ peptides to cross-seed solutions of Aβ was the inverse of their ability to form fibrils on their own (i.e. Aβ ≈ Nα-OA-Aβ >> K16-OA-Aβ >> K28-OA-Aβ). By CD spectroscopy, K16-OA-Aβ and K28-OA-Aβ had increased β-sheet propensity compared with Aβ-(1–40) or Nα-OA-Aβ. K16-OA-Aβ and K28-OA-Aβ were more amphiphilic than Aβ-(1–40) or Nα-OA-Aβ, as shown by lower “critical micelle concentrations” and higher monolayer collapse pressures. Finally, K16-OA-Aβ and K28-OA-Aβ are much more cytotoxic to N2A cells than Aβ-(1–40) or Nα-OA-Aβ. The greater cytotoxicity of K16-OA-Aβ and K28-OA-Aβ may reflect their greater amphiphilicity. We conclude that lipidation can make Aβ more prone to aggregation and more cytotoxic, but these effects are highly site-specific.

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Concentrations of amyloid-β protein in cerebrospinal fluid increase with age in patients free from neurodegenerative disease

Abstract

Epidemiology of Alzheimer's disease

Epidemiol. Rev.

Release of excess amyloid β protein from a mutant amyloid β protein precursor

Science

Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production

Nature

Amyloid β-peptide is produced by cultured cells during normal metabolism

Nature