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Amyloid and tau cerebrospinal fluid biomarkers in HIV infection.

Gisslén M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H - BMC Neurol (2009)

Bottom Line: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups.CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups.Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infectious Diseases, University of Gothenburg, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. magnus.gisslen@infect.gu.se

ABSTRACT

Background: Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods: In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions: Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.

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Hypothesis of alterations in amyloid metabolism in ADC and opportunistic infections compared to AD. The diagram shows proteolytic cleavages of the largest isoform of APP (APP770) and interprets the observed differences in effects of HIV and opportunistic infections from those of Alzheimer's disease on these pathways. In the non-amyloidogenic pathway (a.), cleavage by α-secretase occurs after residue 687, which enables the secretion of the large, soluble ectodomain of APP (sAPPα) into the medium and retention of the 83-residue C-terminal fragment (α-CTF) in the membrane. The α-CTF fragment can undergo cleavage by γ-secretase at residue 711 or 713 to release the p3 peptides (c.). In the amyloidogenic pathway (b.), β-secretase cleaves after residue 671, which causes the secretion of the slightly truncated sAPPβ molecule and the retention of a 99 residue C-terminal fragment (β-CTF). This fragment can undergo further cleavage by γ-secretase to release 40 or 42 aminoacid-long Aβ fragments (c.). Cleavage of both α- and β-CTF by γ-secretase releases the APP intracellular domain (AICD) into the cytoplasm. Hypothesized differences in the steps leading to CSF biomarker changes include: 1. an effect of CNS infection or immune activation on an early step in APP metabolism, in contrast to 2. deposition of Aβ1-42 in Alzheimer's disease[41].
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Figure 4: Hypothesis of alterations in amyloid metabolism in ADC and opportunistic infections compared to AD. The diagram shows proteolytic cleavages of the largest isoform of APP (APP770) and interprets the observed differences in effects of HIV and opportunistic infections from those of Alzheimer's disease on these pathways. In the non-amyloidogenic pathway (a.), cleavage by α-secretase occurs after residue 687, which enables the secretion of the large, soluble ectodomain of APP (sAPPα) into the medium and retention of the 83-residue C-terminal fragment (α-CTF) in the membrane. The α-CTF fragment can undergo cleavage by γ-secretase at residue 711 or 713 to release the p3 peptides (c.). In the amyloidogenic pathway (b.), β-secretase cleaves after residue 671, which causes the secretion of the slightly truncated sAPPβ molecule and the retention of a 99 residue C-terminal fragment (β-CTF). This fragment can undergo further cleavage by γ-secretase to release 40 or 42 aminoacid-long Aβ fragments (c.). Cleavage of both α- and β-CTF by γ-secretase releases the APP intracellular domain (AICD) into the cytoplasm. Hypothesized differences in the steps leading to CSF biomarker changes include: 1. an effect of CNS infection or immune activation on an early step in APP metabolism, in contrast to 2. deposition of Aβ1-42 in Alzheimer's disease[41].

Mentions: APP is an ubiquitously expressed transmembrane protein that undergoes proteolytic processing by different secretases, resulting in generation of metabolites with varying potential pathological consequences (Figure 4) (for review, Andreasson et al [41]). Cleavage by α-secretase leads to production of soluble sAPPα that is shed from the cell membrane and can diffuse into the CSF where its concentration can be measured. This process has been referred to as the non-amyloidogenic pathway since it does not generate pathogenic Aβ. By contrast, cleavage of APP by β-secretase produces sAPPβ, also released and accessible to CSF for measurement, and β-CTF which, after further cleavage by γ-secretase, forms Aβ peptides, including Aβ1-42. In aggregated form, the latter is the major component of Alzheimer's disease plaques and has been proposed as one of the key molecules responsible for neurodegeneration in Alzheimer's disease [38]. CSF levels of sAPPα and sAPPβ are unaltered [42,43] or mildly elevated in sporadic Alzheimer's disease [44]. The reduced CSF Aβ1-42 concentration in Alzheimer's disease patients is speculated to result from deposition of aggregates that are then sequestered in brain, preventing 'normal' levels from reaching the ventriculo-subarachnoid space [45,46].


Amyloid and tau cerebrospinal fluid biomarkers in HIV infection.

Gisslén M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H - BMC Neurol (2009)

Hypothesis of alterations in amyloid metabolism in ADC and opportunistic infections compared to AD. The diagram shows proteolytic cleavages of the largest isoform of APP (APP770) and interprets the observed differences in effects of HIV and opportunistic infections from those of Alzheimer's disease on these pathways. In the non-amyloidogenic pathway (a.), cleavage by α-secretase occurs after residue 687, which enables the secretion of the large, soluble ectodomain of APP (sAPPα) into the medium and retention of the 83-residue C-terminal fragment (α-CTF) in the membrane. The α-CTF fragment can undergo cleavage by γ-secretase at residue 711 or 713 to release the p3 peptides (c.). In the amyloidogenic pathway (b.), β-secretase cleaves after residue 671, which causes the secretion of the slightly truncated sAPPβ molecule and the retention of a 99 residue C-terminal fragment (β-CTF). This fragment can undergo further cleavage by γ-secretase to release 40 or 42 aminoacid-long Aβ fragments (c.). Cleavage of both α- and β-CTF by γ-secretase releases the APP intracellular domain (AICD) into the cytoplasm. Hypothesized differences in the steps leading to CSF biomarker changes include: 1. an effect of CNS infection or immune activation on an early step in APP metabolism, in contrast to 2. deposition of Aβ1-42 in Alzheimer's disease[41].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807422&req=5

Figure 4: Hypothesis of alterations in amyloid metabolism in ADC and opportunistic infections compared to AD. The diagram shows proteolytic cleavages of the largest isoform of APP (APP770) and interprets the observed differences in effects of HIV and opportunistic infections from those of Alzheimer's disease on these pathways. In the non-amyloidogenic pathway (a.), cleavage by α-secretase occurs after residue 687, which enables the secretion of the large, soluble ectodomain of APP (sAPPα) into the medium and retention of the 83-residue C-terminal fragment (α-CTF) in the membrane. The α-CTF fragment can undergo cleavage by γ-secretase at residue 711 or 713 to release the p3 peptides (c.). In the amyloidogenic pathway (b.), β-secretase cleaves after residue 671, which causes the secretion of the slightly truncated sAPPβ molecule and the retention of a 99 residue C-terminal fragment (β-CTF). This fragment can undergo further cleavage by γ-secretase to release 40 or 42 aminoacid-long Aβ fragments (c.). Cleavage of both α- and β-CTF by γ-secretase releases the APP intracellular domain (AICD) into the cytoplasm. Hypothesized differences in the steps leading to CSF biomarker changes include: 1. an effect of CNS infection or immune activation on an early step in APP metabolism, in contrast to 2. deposition of Aβ1-42 in Alzheimer's disease[41].
Mentions: APP is an ubiquitously expressed transmembrane protein that undergoes proteolytic processing by different secretases, resulting in generation of metabolites with varying potential pathological consequences (Figure 4) (for review, Andreasson et al [41]). Cleavage by α-secretase leads to production of soluble sAPPα that is shed from the cell membrane and can diffuse into the CSF where its concentration can be measured. This process has been referred to as the non-amyloidogenic pathway since it does not generate pathogenic Aβ. By contrast, cleavage of APP by β-secretase produces sAPPβ, also released and accessible to CSF for measurement, and β-CTF which, after further cleavage by γ-secretase, forms Aβ peptides, including Aβ1-42. In aggregated form, the latter is the major component of Alzheimer's disease plaques and has been proposed as one of the key molecules responsible for neurodegeneration in Alzheimer's disease [38]. CSF levels of sAPPα and sAPPβ are unaltered [42,43] or mildly elevated in sporadic Alzheimer's disease [44]. The reduced CSF Aβ1-42 concentration in Alzheimer's disease patients is speculated to result from deposition of aggregates that are then sequestered in brain, preventing 'normal' levels from reaching the ventriculo-subarachnoid space [45,46].

Bottom Line: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups.CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups.Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Infectious Diseases, University of Gothenburg, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. magnus.gisslen@infect.gu.se

ABSTRACT

Background: Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods: In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results: CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions: Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.

Show MeSH
Related in: MedlinePlus