Cerebrospinal fluid levels of &bgr;-amyloid(42) in patients with Alzheimer's disease are related to the exon 2 polymorphism of the cathepsin D gene

The intracellular aspartyl protease cathepsin D (catD) is involved in such Alzheimer's disease (AD)-related processes as the activation of the endosomal/lysosomal system and the cleavage of the amyloid precursor protein into amyloidogenic components, which may initiate neurodegeneration. A non-synonymous polymorphism (exon 2, C to T exchange leading to ala→val substitution) of the gene encoding catD (CTSD) was previously associated with AD, in that the T allele increased the risk for AD. To investigate whether the T allele is associated with disease-related traits, we measured the concentration of the amyloid &bgr;-peptide 1-42 (A&bgr;(42)) and 1-40 (A&bgr;(40)) in patients and control subjects. The T allele of the CTSD genotype was associated with a 50% decrease in A&bgr;(42) levels in the cerebrospinal fluid. Thus, we demonstrate a significant impact of the CTSD genotype on A&bgr;(42) levels in the cerebrospinal fluid of AD patients and underpin the importance of the validation of susceptibility genes by examining their potential pathophysiological relevance.

[1]  P. Mathews,et al.  The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A Review , 2000, Neurochemical Research.

[2]  R. Nitsch,et al.  Non-replication of association between cathepsin D genotype and late onset Alzheimer disease. , 2001, American journal of medical genetics.

[3]  M. McInnis,et al.  No evidence for genetic association or linkage of the cathepsin D (CTSD) exon 2 polymorphism and Alzheimer disease , 2001, Annals of neurology.

[4]  R. Nixon,et al.  A “Protease Activation Cascade” in the Pathogenesis of Alzheimer's Disease , 2000, Annals of the New York Academy of Sciences.

[5]  D. Selkoe.  The genetics and molecular pathology of Alzheimer's disease: roles of amyloid and the presenilins. , 2000, Neurologic clinics.

[6]  M. Shearman,et al.  Quantitation of amyloid-β peptides in biological milieu using a novel homogeneous time-resolved fluorescence (HTRF) assay , 2000, Journal of Neuroscience Methods.

[7]  S. Sevush,et al.  The genetic association between Cathepsin D and Alzheimer's disease , 2000, Neuroscience Letters.

[8]  S. DeKosky,et al.  Genetic polymorphisms in the cathespin D and interleukin-6 genes and the risk of Alzheimer's disease , 2000, Neuroscience Letters.

[9]  M. Gold,et al.  Ethnicity-dependent association of the cathepsin D C224T polymorphism with Alzheimer's disease , 2000, Neurobiology of Aging.

[10]  G Lynch,et al.  Novel Cathepsin D Inhibitors Block the Formation of Hyperphosphorylated Tau Fragments in Hippocampus , 2000, Journal of neurochemistry.

[11]  J. Pauls,et al.  A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease , 2000, Annals of neurology.

[12]  H. Wiśniewski,et al.  Plasma and cerebrospinal fluid Levels of amyloid β proteins 1-40 and 1-42 in Alzheimer disease , 2000 .

[13]  K. Blennow,et al.  CSF levels of tau, β-amyloid1–42 and GAP-43 in frontotemporal dementia, other types of dementia and normal aging , 2000, Journal of Neural Transmission.

[14]  G. Sadik,et al.  In vitro processing of amyloid precursor protein by cathepsin D. , 1999, The international journal of biochemistry & cell biology.

[15]  S. McIlroy,et al.  Cathepsin D gene exon 2 polymorphism and sporadic Alzheimer's disease , 1999, Neuroscience Letters.

[16]  F. Jessen,et al.  Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer's disease , 1999, Neuroscience Letters.

[17]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[18]  R. Passmore.  The pleasures of pipe smoking , 1998, The Lancet.

[19]  J. Mcdermott,et al.  Degradation of Alzheimer's beta-amyloid protein by human cathepsin D. , 1996, Neuroreport.

[20]  J. Growdon,et al.  Cerebrospinal fluid levels of amyloid β‐protein in alzheimer's disease: Inverse correlation with severity of dementia and effect of apolipoprotein e genotype , 1995, Annals of neurology.

[21]  Jinhe Li,et al.  Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: Evidence for early up-regulation of the endosomal-lysosomal system , 1995, Neuron.

[22]  M. Zaudig,et al.  SIDAM – A Structured Interview for the diagnosis of Dementia of the Alzheimer type, Multi-infarct dementia and dementias of other aetiology according to ICD-10 and DSM-III-R , 1991, Psychological Medicine.

[23]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[24]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[25]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.