Distinct cerebrospinal fluid amyloid β peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>We measured Aβ isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (<it>PSEN1</it>) 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.</p> <p>Conclusion</p> <p>SAD patients and <it>PSEN1 </it>A431E mutation carriers are characterized by aberrant CSF Aβ isoform patterns that hold clinically relevant diagnostic information. <it>PSEN1 </it>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 <it>PSEN1 </it>A431E mutation modulates γ-secretase cleavage site preference in a disease-promoting manner.</p

Synaptic elimination and the complement system in Alzhaimer's disease

The mechanisms behind Alzheimer’s disease (AD) are largely unknown. The disease is to a large extent hereditary, and the best pathophysiological correlate to the severity of the symptoms is loss of synapses. The general aim of this thesis was to examine the hypothesis that AD is primarily a synaptic disease – with an emphasis on complement-mediated elimination of synapses. Animal models of AD have shown that long-term potentiation (LTP) of synapses is inhibited by beta amyloid (Aβ). LTP is considered to be a physiological correlate to learning and memory, and Aβ is a peptide that constitute the extracellular plaques that characterise AD. The Aβ induced inhibition of LTP has been shown to be dependent on the receptor for advanced glycation end products (RAGE). In the present thesis I present results that suggest an association of a functional single nucleotide polymorphism (SNP) in the gene encoding RAGE with diagnosis of AD. Thus linking the synapse related pathophysiology observed in animal models, to human patients with AD. During development, synapses in the retinogeniculate system and the sensorimotor cortex of mice are eliminated in a complement mediated manner. Since AD pathology primarily affects the hippocampus, we sought to investigate whether the complement system mediates elimination of hippocampal synapses as well. Indeed, by use of complement component 3 (C3) deficient mice, electrophysiological, histological, molecular and behavioural methods, we obtained results that suggest this for a fact. Considering the importance of synapse loss in AD we decided to measure the levels of the complement proteins C3, complement component 4 (C4), complement factor B (CFB) and complement receptor 1 (CR1) in cerebrospinal fluid (CSF) from patients with various degrees of AD. The results showed a trend towards increased complement levels in AD patients. This association, however, was too weak to be of diagnostic value. Nevertheless it supports the notion of complement involvement in AD. Next we hypothesised that genetic variation in genes encoding complement proteins could potentially be associated with diagnosis of AD. Therefore, we investigated SNPs in the complement genes CR1, C3, CFB, and the second complement component (C2). Although no such associations were found, we did, however, find an association of C2/CFB SNPs with measures of cognitive function (MMSE) and neuronal damage (tau) in AD patients, thus lending further support for the hypothesis of complement mediated synaptic elimination in AD. I conclude that several lines of evidence suggest that AD might very well be the result of aberrant complement regulation, with improper synaptic elimination as a consequence. Precise knowledge about the mechanisms underlying AD is of great value to research into accurate diagnostic methods and treatments, thus, further research on the subject of synapse elimination in AD is warranted

Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease

Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers A beta 42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful

Association of the RAGE G82S polymorphism with Alzheimer\u27s disease

The receptor for advanced glycation end-products (RAGE) has been implicated in several pathophysiological processes relevant to Alzheimer\u27s disease (AD), including transport and synaptotoxicity of AD-associated amyloid beta (A beta) peptides. A recent Chinese study (Li et al. in J Neural Transm 117:97-104, 2010) suggested an association between the 82S allele of the functional single nucleotide polymorphism (SNP) G82S (rs2070600) in the RAGE-encoding gene AGER and risk of AD. The present study aimed to investigate associations between AGER, AD diagnosis, cognitive scores and cerebrospinal fluid AD biomarkers in a European cohort of 316 neurochemically verified AD cases and 579 controls. Aside from G82S, three additional tag SNPs were analyzed to cover the common genetic variation in AGER. The 82S allele was associated with increased risk of AD (P (c) = 0.04, OR = 2.0, 95% CI 1.2-3.4). There was no genetic interaction between AGER 82S and APOE epsilon 4 in producing increased risk of AD (P = 0.4), and none of the AGER SNPs showed association with A beta(42), T-tau, P-tau(181) or mini-mental state examination scores. The data speak for a weak, but significant effect of AGER on risk of AD

Complement Gene Single Nucleotide Polymorphisms and Biomarker Endophenotypes of Alzheimer\u27s Disease

The complement system has been implicated in both physiological synapse elimination and Alzheimer\u27s disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease intensity/severity

Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.

Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance