The Aggregation Inhibitor Peptide QBP1 as a Therapeutic Molecule for the Polyglutamine Neurodegenerative Diseases

Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Alzheimer’s disease: the new promise

Clinical vignette: A 59-year-old aeronautical engineer is referred to you for evaluation because of increasing difficulty with job performance over the last several years. Difficulty managing home finances, getting lost driving, and forgetting appointments have become common. Previously outgoing, he is now depressed and irritable. After appropriate neurologic assessment, including brain imaging and metabolic studies, you make the diagnosis of Alzheimer’s dementia and are asked by the patient’s family what treatment is available

Toxicity of expanded polyglutamine-domain proteins in Escherichia coli

Five neurodegenerative diseases are caused by proteins with expanded polyglutamine domains. Toxicity of these proteins has been previously identified only in mammals, and no simple model systems are available. In this paper, we demonstrate in E. coli that long polyglutamine domains (59–81 residues) as GST-fusion proteins inhibit growth while smaller glutamine (10–35 residues) or polyalanine (61 residues) domains have no effect. Analogously in humans, polyglutamine repeats less than 35–40 glutamines produce a normal phenotype, while expansion greater than 40 glutamines is always associated with disease. Expression of polyglutamine proteins in E. coli may help identify the molecular mechanism of pathogenesis of CAG trinucleotide repeat diseases and be a useful screen to identify potential therapeutic compounds

Apolipoprotein E E4 Allele and Risk of Dementia

To the Editor.—In response to the letter by Dr Frisoni and colleagues1 that reported a series of 42 vascular dementia patients with an apolipoprotein E (apo E)E4 allele frequency equivalent to that reported for Alzheimer's disease (AD), we believe that their cases represent AD patients who share a clinically suggested diagnosis of vascular dementia.Frisoni et al do not provide convincing evidence that their patients diagnosed as having vascular dementia do not also have AD. The cited "research criteria" (NINDS-AIREN2) provide for a diagnosis of probable or possible vascular dementia during life. These research criteria have yet to be tested with postmortem validation. It should also be noted that Roman and Tatemichi, coauthors of the published NINDS-AIREN criteria, more recently commented that the "criteria do not dismiss the coexistence of AD and vascular dementia."3 Roman and Tatemichi also commented that "in the absence of laboratory test