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SUMMARY:Molecular Biological and Molecular Genetic studies of the Mechanis
 ms Underlying  Neurodegeneration in Alzheimer's Disease - Prof. Peter Hysl
 op  Cambridge Institute for Medical Research
DTSTART:20101020T093000Z
DTEND:20101020T103000Z
UID:TALK27027@talks.cam.ac.uk
CONTACT:benedetta bolognesi
DESCRIPTION:\nEpidemiological studies of AD have revealed that the two str
 ongest risk factors are increasing age and a positive family history. Whil
 e a positive family history does not necessarily imply inherited factors\,
  molecular genetic tools have been applied to familial aggregates of AD du
 ring the past 30 years. These tools\, beginning first with genetic linkage
  studies in early onset autosomal dominant pedigrees have revealed that mi
 ssense mutations in the amyloid precursor protein (APP)\, presenilin-1 (PS
 1)\, and presenilin-2 (PS2) are capable of causing this disease. Biochemic
 al analyses of the effects of these mutations tells a convincing story tha
 t misprocessing of APP\, and the overproduction of aggregation-prone Abeta
  peptide is an important causative factor at least in this form of AD. Thi
 s knowledge has in turn spurred on efforts to generate disease-modifying t
 herapies for AD based upon blocking the production/effect of Abeta. \n\nSu
 bsequent studies using case:control designs to test associations with cand
 idate genes have led to the discovery that the E4 allele of Apolipoprotein
  E (APOE ε4) is strongly associated with late onset AD (and is in fact th
 e strongest genetic risk factor known to date). Similar studies with multi
 ple other candidate genes have indicted a long list of these genes\, sever
 al of which (SORL1\, SORCS1\, ACE1 amongst them) appear to be reasonably r
 obust\, having been replicated in several independent series. More recentl
 y\, hypothesis-free genome-wide association studies (GWAS) have been appli
 ed\, and have reported confirmed associations with PICALM\, clusterin (CLU
 /APOEJ) and complement receptor 1 (CR1). Some useful questions can address
 ed with these new AD genes. First of all\, do they act in Abeta-generating
  pathways? Are they part of the downstream effector pathways by which Abet
 a acts? Are they in pathways that cause Alzheimer’s disease completely i
 ndependent of Abeta? Answers to these questions will be identified once th
 e disease-causing mutations are known\, and can be assessed in cellular an
 d animal models.  The identification of the remaining genes that underlie 
 the unaccounted-for genetic risk poses a more difficult problem. \n
LOCATION:Unilever Lecture Theatre\,  Department of Chemistry
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