Peter St George-Hyslop

Aβ peptide immunization reduces behavioural impairment and plaquesin a model of Alzheimer's disease

Much evidence indicates that abnormal processing and extracellular deposition of amyloid-β peptide (Aβ), a proteolytic derivative of the β-amyloid precursor protein (βAPP), is central to the pathogenesis of Alzheimers disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimers disease, immunization with Aβ causes a marked reduction in burden of the brain amyloid. Evidence that Aβ immunization also reduces cognitive dysfunction in murine models of Alzheimers disease would support the hypothesis that abnormal Aβ processing is essential to the pathogenesis of Alzheimers disease, and would encourage the development of other strategies directed at the ‘amyloid cascade’. Here we show that Aβ immunization reduces both deposition of cerebral fibrillar Aβ and cognitive dysfunction in the TgCRND8 murine model of Alzheimers disease without, however, altering total levels of Aβ in the brain. This implies that either a ∼50% reduction in dense-cored Aβ plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic Aβ species.

TREM2 Variants in Alzheimer's Disease

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimers disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimers disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimers disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimers disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimers disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimers disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimers disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimers disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimers disease. (Funded by Alzheimers Research UK and others.).

Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP.

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid β peptide (Aβ) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Functional variants of OCTN cation transporter genes are associated with Crohn disease

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of ∼250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G→C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.

γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?

Investigations into the proteolytic processing of amyloid precursor protein (APP) have provided insights into both the pathogenesis of Alzheimers disease and an unusual form of regulated proteolytic processing within the membrane-spanning domains of several proteins, including APP, Notch and ErbB4. Some of the enzymes responsible for α- and β-secretase cleavage have been identified, and these seem to be conventional proteolytic events. However, the molecular events that are involved in γ-secretase cleavage within the transmembrane domain of these proteins are much more complex. The presenilins and nicastrin are required for this process, but the role of the presenilins remains unclear. Although some data support the idea that the presenilins are in fact the active site of γ-secretase, other data indicate that they might have a more indirect role — for example, in transporting substrates to the correct subcellular compartments for γ-secretase cleavage.

Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response.

Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer’s disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer’s disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

α-Synuclein Membrane Interactions and Lipid Specificity

With the discovery of missense mutations (A53T and A30P) in α-synuclein (α-Syn) in several families with early onset familial Parkinsons disease, α-Syn aggregation and fibril formation have been thought to play a role in the pathogenesis of α-synucleinopathies, such as Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy. As previous reports have suggested that α-Syn plays a role in lipid transport and synaptic membrane biogenesis, we investigated whether α-Syn binds to a specific lipid ligand using thin layer chromatography overlay and examined the changes in its secondary structure using circular dichroism spectroscopy. α-Syn was found to bind to acidic phospholipid vesicles and this binding was significantly augmented by the presence of phosphatidylethanolamine, a neutral phospholipid. We further examined the interaction of α-Syn with lipids by in situ atomic force microscopy. The association of soluble wild-type α-Syn with planar lipid bilayers resulted in extensive bilayer disruption and the formation of amorphous aggregates and small fibrils. The A53T mutant α-Syn disrupted the lipid bilayers in a similar fashion but at a slower rate. These results suggest that α-Syn membrane interactions are physiologically important and the lipid composition of the cellular membranes may affect these interactions in vivo.

Lewy Bodies Contain Altered α-Synuclein in Brains of Many Familial Alzheimer’s Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes

Missense mutations in the alpha-synuclein gene cause familial Parkinsons disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimers disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.

Molecular Genetics of Alzheimer’s Disease

Application of genetic paradigms to Alzheimers disease (AD) has led to confirmation that genetic factors play a role in this disease. Additionally, researchers now understand that AD is genetically heterogeneous and that some genetic isoforms appear to have similar or related biochemical consequences. Genetic epidemiologic studies indicate that first-degree relatives of AD probands have an age-dependent risk for AD approximately equal to 38% by age 90 years (range 10% to 50%). This incidence strongly suggests that transmission may be more complicated than a simple autosomal dominant trait. Nevertheless, a small proportion of AD cases with unequivocal autosomal dominant transmission have been identified. Studies of these autosomal dominant familial AD (FAD) pedigrees have thus far identified four distinct FAD genes. The beta-amyloid precursor protein (beta APP) gene (on chromosome 21), the presenilin 1 (PS1) gene (on chromosome 14), and the presenilin 2 (PS2) gene (on chromosome 1) gene are all associated with early-onset AD. Missense mutations in these genes cause abnormal beta APP processing with resultant overproduction of A beta 42 peptides. In addition, the epsilon 4 allele of apolipoprotein E (APOE) is associated with a increased risk for late-onset AD. Although attempts to develop symptomatic treatments based on neurotransmitter replacement continue, some laboratories are attempting to design treatments that will modulate production or disposition of A beta peptides.