John Hardy on Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.
COMMENT A heroic and painstaking study… but we still don't really know what APP does. J.Hardy 0 ...
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John Hardy on Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.
COMMENT Now proven almost beyond reasonable doubt: presenilin = gamma secretase. The three papers almost establish beyond reasonable doubt that presenilins are the long-sort after gamma secretases. The questions that remain include what are the other components ...
John Hardy on Reduction of Abeta accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin.
COMMENT "An interesting paper which shows yet another way of reducing plaque load... as a result of the transgenic work, there are now many hopeful avenues for the drug industry and academics to look for Alzheimer treatments." J.Hardy 0 ...
John Hardy on Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy.
COMMENT An amazing technology used to show, once and for all, that plaques are dynamic structures. A great paper which subverts the huge literature seeking to correlate plaque numbers with clinical features. Pathology does not wait around to be counted!!!" J ...
John Hardy on Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation.
COMMENT "An excellent paper, not only establishing BACE as b-secretase but also suggesting that knockout (or, by implication drug inhibition) may not have major adverse effects." J.Hardy 0 ...
John Hardy on Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle.
COMMENT A fascinating paper which starts to move the study of inclusion body myositis on from phenomenology. J.Hardy 0 ...
John Hardy on Tau is essential to beta -amyloid-induced neurotoxicity.
COMMENT An interesting paper... it would be good to know, though, whether tau was "essential" to other forms of induced neurotoxicity. J.Hardy 0 ...
John Hardy on SNP association studies in Alzheimer's disease highlight problems for complex disease analysis.
COMMENT "At last, a welcome attempt to try and deal with the problems of multiple testing in association studies." J.Hardy 0 ...
John Hardy on beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease.
COMMENT A fascinating study which further emphasises the parallels between tau andsynuclein pathobiology: mutations in both genes lead to pathology, haplotypes at both genes predispose to sporadic disease, both pathologies occur 'downstream' in ...
John Hardy on Prion protein protects human neurons against Bax-mediated apoptosis.
COMMENT It will be interesting to see whether doppel antagonises this effect. J.Hardy 0 ...
John Hardy on A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease.
COMMENT An extremely important paper which provides the experimental evidence that cholesterol lowering drugs may be beneficial to Alzheimer's disease..... while this paper does not use statins, the treatment implications are clear. From a basic science ...
John Hardy on tau Exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5' and 3' splice sites.
COMMENT This is an interesting and thorough paper discussing the details of tau splicing regulation. However, it comes to the suprising, and probably erroneous conclusion that there is not a stem look structure at the exon 10 splice site, but rather, that the ...
John Hardy on Identification of a novel family of presenilin homologues.
COMMENT While the homology between these proteins and PS1 and PS2 is not great, their importance is that their occurrence suggests there may be many other regulated membrance cleavage pathways and detailed comparisons may also give mechanistic insights into the ...
John Hardy on A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain.
COMMENT This is an exciting, if expensive method which allows real time visualisation of plaques J.Hardy 0 ...
John Hardy on Determinants of 4-repeat tau expression. Coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion.
COMMENT The importance of the control of tau splicing is clearly critical to the understanding of tau biology in tangle diseases. This is a complex and tightly controlled process as this reference illustrates. J.Hardy 0 ...