| [Obejectives] A common pathogenetic mechenism of Alzheimer's disease (AD) and Creutzfelt-Jakob Disease (CJD) is the accumulation in the brain of abnormally folded proteins leading to neurodegeneration. Aggregations of β-amyloid and PrPSC are the main pathological features in AD and CJD respectively. PrPSC is transformed by conformational change from PrPc, which is the normal form of prion protein encoded by prion protein gene ( PRNP ). Evidences suggested that PRNP polymorphism was not only important for CJD but also for AD. But it remains unclear whether PRNP codon 129 polymorphism is a risk factor for onset of AD. Furthermore, the normal function of PrPc and PrPc's role in AD pathogenesis remain unclear. In this paper, the correlation of PRNP codon 129 polymorphism and onset of AD were investigated for better understanding of the underlying relationship between CJD and AD. Neuropathological work was also done to discover whether PrPc plays neuroprotective roles in AD and brain aging.[Materials and Methods] The polymorphism of PRNP codon 129 was investigated by PCR-RFLP in a total of 182 senile Han subjects of military health-care population in Beijing, which was composed of 92 cognitively healthy controls, 60 individuals with a clinical diagnosis of AD and 30 cases of vascular dementia. ApoE gene polymorphism was also detected for stratification. For neuropathological study, 5 brains of middle aged ( <60 years old ), 13 of aged ( 60-74 years old ) and 14 of elderly aged ( ≥75 years old ) subjects who died without clinical or pathological involvement of central nervous system and 14 brains of AD patients were obtained at autopsy. Frontal lobe and hippocampus were mainly investigated. HE, Aβ, hyperphosphorylated Tau ( clone AT8 ) and Gallyas-Braak staining were used for morphological observation and diagnosticascertainment. Immunostaining was carried out to observe the expression of PrPc, HO-1 ( index for oxidative stress ) and Bax ( index for apoptosis ). Positive expression degree and IOD value were observed. Double staining with immuno-histochemistry-immunoflurescence or immunoflurescence-immunoflurescence was used to analyze coexpression of PrPc-Aβ/Tau/HO-1/Bax, HO-1-Tau/Bax/ GFAP, and Bax-Tau.[Results]1.The genotype frequencies of PRNP codon 129 of senile Han subjects of military health-care population in Beijing were 93.96% MM, 6.04% MV and 0%VV, with distribution of 95% MM and 5% MV in LOAD group.2.The risk of MM carrier for LOAD increased slightly but without statistical significance before stratification by ApoEε4 (OR=1.33, 95% CI=0.32-5.49 ). After stratifying by ApoEε4 carrier status, the risk of MM carrier for LOAD increased slightly but still without statistical significance either in ApoEε4 positive ( OR=4.75, 95% CI=0.35-65.13 ) or ApoEε4 negative subjects ( OR=2.26, 95% CI=0.27-18.96).3.Logistic regression analysis using age, gender and ApoEε4 allele as covariates showed OR value of 3.27 ( 95%CI=0.402～26.605, P value=0.2627 ) of MM genotype for LOAD.4.PrPc expressed within neurons of frontal lobe and hippocampus in aged, elderly aged and AD cases. PrPc didn't express in senile plaque.5. The positive expression degree of PrPc, HO-1 and Bax differed significantly between different groups respectively ( P<0.05 ). There were statistically significant correlations of positive expression degree between PrPc -HO-1, and PrPc-Bax in hippocampus of aged, elderly aged and AD groups ( P<0.05 ). IOD values of PrPc, HO-1 and Bax were significantly increased in AD cases compared with controls ( P<0.05 ). There were no significant IOD value differences of PrPc, HO-1 and Bax in frontal lobe within each group ( P>0.05 ), also in hippocampus of aged group ( P>0.05 ). But in hippocampus of elderlyaged group, IOD value of HO-1 was significantly increased compared with PrPc ( P<0.05 ). There was neither significant IOD value difference between PrPc and Bax in hippocampus of elderly aged and AD groups, nor between PrPc and HO-1 in hippocampus of AD ( P>0.05 ).6. Coexpression of PrPc and Tau existed mainly in pre-tangle stage neurons of hippocampus of AD. Coexpressions of PrPc-HO-1 and PrPc-Bax could also been detected in frontal lobe and hippocampus of elderly aged and AD groups.7. There were coexpressions of HO-1 and Tau/GFAP. Coexpressions of Bax and Tau /HO-1 were absent. Some microgliocytes were Bax-positive.[Conclusions]1.There was significant increment of PRNP codon 129 M allele and decrement of V allele in senile Han subjects of military health-care population in Beijing compared with European population. PRNP codon 129 polymorphism of East Asia population was significantly different from that of Europe.2.The risk for LOAD of individuals carrying PRNP codon 129 MM genotype was not increased significantly. PRNP codon 129 MM genotype was not an isolated risk factor for onset of LOAD.3. PrPc expressed in neurons of aging and AD Brain but did not expressed in senile plaque.4. PrPc, HO-1 and Bax were upregulated in aged, elderly aged and AD cases with a tendency to increase with brain aging.5. PrPc may play a role of neuroprotection against neurofibrillary tangle formation, oxidative stress and apoptosis in the progression of AD and brain aging. |
