RESUMEN
BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Atención/fisiología , Trastornos del Conocimiento/genética , Función Ejecutiva/fisiología , Anciano , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Cromosomas Humanos Par 21/genética , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , LinajeRESUMEN
Genetic evidence indicates a central role of cerebral accumulation of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with gamma-secretase activity, the enzymatic complex generating Abeta. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age-matched controls (n=253), sporadic AD (SAD, n=256) and familial AD (FAD, n=140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele epsilon4 of apolipoprotein E than controls. The pathogenic role of the PEN-2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Mutación , Anciano , Secretasas de la Proteína Precursora del Amiloide , Secuencia de Bases , Western Blotting , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Linaje , Polimorfismo Genético , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Perinatal hypoxic injury is the major cause of normal neural developmental alterations. Recent studies concerning animal models show that an hypoxic/ischaemic event triggers a process taking to a synaptic architecture reorganization which induces a transient change in the synaptic (synapsin 1, SNAP 25, APP) and neuronal (MAP2, N-CAM, GAP-43 and presenilins) protein expression. Here we review the post-translational modifications of some proteins after hypoxic-ischaemic events. A deeper study on synaptic proteins plasticity could give an important key for the understanding of the recovery mechanisms of the nervous system.
Asunto(s)
Hipoxia-Isquemia Encefálica/etiología , Proteínas del Tejido Nervioso/fisiología , Péptidos beta-Amiloides/fisiología , Modelos Animales de Enfermedad , Proteína GAP-43/fisiología , Humanos , Proteínas de la Membrana/fisiología , Proteínas Asociadas a Microtúbulos/fisiología , Moléculas de Adhesión de Célula Nerviosa/fisiología , Presenilina-1 , Presenilina-2 , Sinapsinas/fisiología , Proteína 25 Asociada a SinaptosomasRESUMEN
The influence of hypothyroidism (HO) induced by treatment with propylthiouracil on lipid composition, receptor responsiveness of M1-muscarinic receptors (M1AChRs) and metabotropic glutamate receptors (mGluRs) as well as on protein kinase C (PKC) activity was investigated in the cerebral cortex of Lewis rats. HO did not influence the lipid composition. There was a significant 2-fold increase of efficacy and 6-fold decrease of potency of carbachol-induced inositol phosphate (IP) accumulation in HO, with respect to control rats. The efficacy of trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD)-induced IP accumulation was also higher in HO (by 50%), without differences in EC50 values. The activities of soluble calcium-dependent and calcium-independent PKC were higher in HO than in control rats (both roughly 30%); membrane-associated PKCs were not modified. The data indicate that HO induces an increased responsiveness of M1AChRs and mGluRs and a rise in the soluble PKC activity that could be available and ready for translocation.