Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations (original) (raw)
Related papers
2020
Background: Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ 1-43 is more prone to aggregation and has higher toxic properties than the long-known Aβ 1-42. However, a direct effect on Aβ 1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods: N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ 1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ 1-42 and Aβ 1-40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers. Results: A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ 1-43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ 1-43 levels positively correlated with CSF Aβ 1-42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ 1-43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ 1-43 and Aβ 1-42 levels, we could reclassify as "likely pathogenic" 3 of the unclear mutations.
Human Mutation, 2006
The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid β precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Aβ42 to Aβ40 (Aβ42/Aβ40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Aβ and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible ELISA-based in vitro method and also sought correlation with brain Aβ analyzed by image densitometry and mass spectrometry. All mutations significantly increased Aβ42/Aβ40 in vitro by significantly decreasing Aβ40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. Only for half of the mutations tested, a significant increase in absolute levels of Aβ42 was observed. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Aβ42/Aβ40 (r = -0.89; P = 0.001) and absolute levels of Aβ42 (r = -0.83; P = 0.006), but directly with Aβ40 levels (r = 0.69; P = 0.035). These changes also partly correlated with brain Aβ42 and Aβ40 levels. Together our data suggested that Aβ40 might be protective by perhaps sequestering the more toxic Aβ42 and facilitating its clearance. Also, the in vitro method we described here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting.
Brain Research, 2010
Cerebrospinal fluid (CSF) biomarkers are now widely used for diagnosis of Alzheimer disease (AD) in atypical clinical forms, for differential and early diagnosis, or for stratification of patients in clinical trials. Among these biomarkers, different forms of amyloid peptides (Aβ) produced by the cleavage of a transmembrane precursor protein called APP (amyloid precursor protein) have a major role. Aβ peptides exist in different length the most common ones having 40 (Aβ40), 42 (Aβ42), or 38 (Aβ38) amino acids in length. APP processing by gamma-secretase releases also an amino-terminal secreted fragment called sAβPP-beta while an alternative nonamyloidogenic cleavage of APP, through an alpha-secretase, liberates another fragment called sAβPP-alpha. To decipher the molecular and pathological mechanisms leading to the production and the detection of these entities is essential for the comprehension and the prevention of AD. In this report, we present the results of the Keywords: Biomarkers CSF Soluble amyloid precursor proteins Aβ fragment peptides Alzheimer disease Dementia B R A I N R E S E A R C H 1 3 5 7 ( 2 0 1 0 ) 1 7 5 -1 8 3 ⁎ Corresponding authors. A. Gabelle is to be contacted a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m w w w . e l s e v i e r . c o m / l o c a t e / b r a i n r e s multiplex measurement of CSF Aβ38, Aβ40, Aβ42, sAβPP-alpha, and sAβPP-beta in 60
Neuroscience Letters, 1995
The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and neurofibrillary tangles. The main constituent of senile plaques is amyloid /I-peptide (q8) and in recent years, pathogenic mutations in the arnyloid precursor protein (APP) gene have been discovered in some AD families. The APP6701671 mutation, found in a Swedish AD family, has revealed overproduction of &I as one pathogenic mechanism for the development of AD. In the present study we have used an immunoassay to measure A/l levels in cerebrospinal fluid (CSF) from APPe70,bT1 mutation-carriers and non-carriers. A correlation was seen between ,&PYPOPP in AR l~.,~la m,rl r-h~rstinn nf rlir~nc~ rrlthm,nh nn Iliffa-z=nc-o u,,zc fm,nrl in IP.,P~c nf AR h..aptw~~n thn ~rn,,n~ IlA < L '2-2 nnlml "I.
Molecular Neurodegeneration, 2010
Background: Alzheimer's disease (AD) is associated with deposition of amyloid β (Aβ) in the brain, which is reflected by low concentration of the Aβ1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Aβ peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Aβ. Here, we test the hypothesis that AD is characterized by a specific CSF Aβ isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups. Results: We measured Aβ isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FADassociated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Aβ1-42 and high levels of Aβ1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Aβ1-42 and Aβ1-16, but FAD mutation carriers exhibited very low levels of Aβ1-37, Aβ1-38 and Aβ1-39. Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Aβ isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Aβ1-37, Aβ1-38 and Aβ1-39; fragments that are normally produced by γ-secretase, suggesting that the PSEN1 A431E mutation modulates γ-secretase cleavage site preference in a disease-promoting manner.
Heteromers of amyloid precursor protein in cerebrospinal fluid
Molecular neurodegeneration, 2015
Soluble fragments of the amyloid precursor protein (APP) generated by α- and β-secretases, sAPPα and sAPPβ, have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for the clinical diagnosis of Alzheimer's disease (AD). However, the capacity of these soluble proteins to assemble has not been explored and could be relevant. Our aim is to characterize possible sAPP oligomers that could contribute to the quantification of sAPPα and sAPPβ in CSF by ELISA, as well as to characterize the possible presence of soluble full-length APP (sAPPf). We employed co-immunoprecipitation, native polyacrylamide gel electrophoresis and ultracentrifugation in sucrose density gradients to characterize sAPP oligomers in CSF. We have characterized the presence of sAPPf in CSF from NDC and AD subjects and demonstrated that all forms, including sAPPα and sAPPβ, are capable of assembling into heteromers, which differ from brain APP membrane-dimers. We measured sAPPf, sAPPα and sAPPβ by E...
Enhanced generation of intracellular Aβ42 amyloid peptide by mutation of presenilins PS1 and PS2
European Journal of Neuroscience, 2004
The accumulation of amyloid b-peptide (Ab) in the brain is a critical pathological process in Alzheimer's disease (AD). Recent studies have implicated intracellular Ab in neurodegeneration in AD. To investigate the generation of intracellular Ab, we established human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid precursor protein (APP), Swedish mutant APP, APP plus presenilin 1 (PS1) and presenilin 2 (PS2; wild-type or familial AD-associated mutant), and quanti®ed intracellular Ab40 and Ab42 in formic acid extracts by sensitive Western blotting. Levels of both intracellular Ab40 and Ab42 were 2±3-fold higher in cells expressing Swedish APP, compared with those expressing wild-type APP. Intracellular Ab42/Ab40 ratios were approximately 0.5 in these cells. These ratios were increased markedly in cells expressing mutant PS1 or PS2 compared with those expressing their wild-type counterparts, consistent with the observed changes in secreted Ab42/Ab40 ratios. High total levels of intracellular Ab were observed in cells expressing mutant PS2 because of a marked elevation of Ab42. Immuno¯uorescence staining additionally revealed more intense Ab42 immunoreactivity in mutant PS2-expressing cells than in wild-type cells, which was partially colocalized with immunoreactivity for the trans-Golgi network and endosomes. The data collectively indicate that PS mutations promote the accumulation of intracellular Ab42, which appears to be localized in multiple subcellular compartments. Materials and methods Antibodies A monoclonal antibody to APP was obtained from Roche Diagnostics (Mannheim, Germany). Polyclonal antibodies to PS1 (Ab111) and PS2 (Ab333) were generated and puri®ed as described previously (Chui et al., 1998; Shirotani et al., 1999). Three Ab-speci®c monoclonal antibodies were used: BA27 (speci®c for Ab40); BC05
Aβ43 levels determine the onset of pathological amyloid deposition
Research Square (Research Square), 2022
Background While most Alzheimer's disease cases are sporadic with late onset (LOAD), ~ 2% of cases are inherited, have an early onset, and are caused by mutations in Presenilins (PSEN1/2) or Amyloid-β Precursor Protein (APP) genes (familial AD, FAD). PSEN1/2 are the catalytic component of γ-secretase, a protease that generates Aβ peptides of different length from APP. Aβ peptides are the major components of amyloid plaques, a pathological lesion that characterizes AD. Analysis of mechanisms by which PSEN1/2 and APP mutations affect Aβ peptide compositions lead to the implication of the absolute or relative increase in Aβ42 levels in amyloid-β plaques formation and AD pathogenesis. The age at onset of FAD depends on the mutation and can differ by decades, suggesting a link between age at onset of dementia and the effects of distinct FAD mutations on Aβ species pro les. It is reasonable to presume that Aβ peptide compositions that initiate amyloid pathology and disease in FAD patients can also inform about disease mechanisms driving the more common LOAD cases. Methods Here, to elucidate the formation of pathogenic Aβ cocktails leading to amyloid pathology, we utilized rat knock-in models of FAD carrying the Swedish APP (App s allele) and the PSEN1 L435F (Psen1 LF allele) mutations. To accommodate the possibility of differences in pathogenicity of rodent and human Aβ, these rat models are genetically engineered to express human Aβ species as both the Swedish mutant allele and the wild-type rat allele (called App h) have been humanized in the Aβ-coding region. Results Analysis of the 8 possible FAD mutant permutations demonstrates correlations between mutation-driven alterations in Aβ pro les and amyloid pathology, and indicates that the CNS levels of Aβ43, rather than absolute or relative increases in Aβ42, determine the onset of pathological amyloid deposition. Conclusions This study corroborates the critical pathological importance of alterations in the Aβ peptides composition, helps clarifying the molecular determinants initiating amyloid pathology, and supports therapeutic interventions targeting Aβ43 to prevent, delay, or revert AD.