Nobuyuki Sodeyama

Lack of association of neprilysin polymorphism with Alzheimer's disease and Alzheimer's disease-type neuropathological changes

Sporadic Alzheimers disease is a polygenic disease and the relation between many genetic risk factors and the development of Alzheimers disease has been controversial. Accumulation of amyloid β-protein (Aβ) in the brain is the neuropathological hallmark and thought to be a key event in the upstream stage of pathological cascade of the disease. Although increased production of Aβ is established in the pathogenesis of familial Alzheimers disease due to mutations in presenilin 1, 2, and amyloid β-protein precursor genes, there is no evidence of up regulated synthesis of Aβ in the brains of patients with sporadic Alzheimers disease. In addition, aging is the most major risk factor for the disease. These findings suggest the possibility that reduction of the catabolic system of Aβ due to aging causes the formation of senile plaques in sporadic disease. Therefore, proteolytic enzymes of Aβ might be related to the development of sporadic Alzheimers disease. One of the enzymes responsible for the degradation of Aβ is neprilysin (NEP).1 This is a membrane bound metallopeptidase which is widely expressed in many tissues including the CNS. It cleaves Aβ 1–42 between amino acids 9 and 10 and between amino acids 37 and 38.2 Reduced mRNA and protein concentrations of NEP in the brain from patients with Alzheimers disease were reported, suggesting that low concentrations of NEP contributed to the accumulation of Aβ.3 Recent investigation showed that NEP inhibitor infusion into the brain resulted in increased deposition of Aβ, indicating that NEP regulates proteolytic catabolism of Aβ in vivo.2 There is a dinucleotide repeat polymorphism in the 5′ region of the NEP gene. A lower molecular weight allele of NEP gene polymorphism is associated …

Senile Dementia of the Neurofibrillary Tangle Type: A Comparison with Alzheimer’s Disease

A subset of senile dementia, ‘senile dementia (SD) of the neurofibrillary tangle (NFT) type’ (SD-NFT), is characterized by numerous NFTs in the hippocampal region and absence or scarcity of senile plaques throughout the brain. To elucidate the pathogenesis of SD-NFT in comparison with Alzheimer’s disease (AD), we investigated the hippocampal lesions and analyzed the tau gene. The hippocampal regions from 5 patients with SD-NFT were neuropathologically evaluated in comparison with AD and nondemented control subjects. The tau gene was analyzed in 3 patients with SD-NFT. The densities of NFTs in the CA1/subiculum and entorhinal cortex of SD-NFT were significantly higher than those in AD. However, hippocampal atrophy, neuronal and synaptic loss, and astrocytic and microglial proliferation in SD-NFT were significantly mild compared with AD. There was no significant difference between SD-NFT and AD in the immunoreactivities of NFTs with different anti-tau antibodies. No mutation was found in the tau gene from the SD-NFT patients. Our results indicate that the neurodegenerative process with NFT formation of the hippocampal region in SD-NFT would be different from that in AD.

Association of a polymorphism of the transforming growth factor-β1 gene with cerebral amyloid angiopathy

Background: A recent study showed that transforming growth factor-β1 (TGF-β1) induces amyloid-β deposition in cerebral blood vessels and meninges of a transgenic mouse model of Alzheimer’s disease (AD), and that TGF-β1 mRNA levels are correlated with cerebral amyloid angiopathy (CAA) in human AD brains. A T/C polymorphism at codon 10 in exon 1 of the TGF-β1 gene has been reported to be associated with the serum TGF-β1 concentration. We investigated whether the TGF-β1 polymorphism is associated with the risk of CAA. Methods: The association between the severity of CAA and the T/C polymorphism at codon 10 in exon 1 of the TGF-β1 was investigated in 167 elderly Japanese autopsy cases, including 73 patients with AD. The apolipoprotein E (APOE) genotype was also determined. Results: The genotypes (TT/ TC/ CC) were associated with the severity of CAA significantly in all patients (p  =  0.0026), in non-AD patients (p  =  0.011), and APOE non-ε4 carriers (p  =  0.0099), but not in AD patients or APOE ε4 carriers. The number of the T alleles positively correlated with the severity of CAA in all patients (p  =  0.0011), non-AD patients (p  =  0.0026), and APOE non-ε4 carriers (p  =  0.0028), but not in AD patients or APOE ε4 carriers. The polymorphism was not significantly associated with AD. Conclusions: Our results suggest that the polymorphism in TGF-β1 is associated with the severity of CAA, especially in non-AD patients and APOE non-ε4 carriers.

Association of Presenilin-1 Polymorphism With Cerebral Amyloid Angiopathy in the Elderly

BACKGROUND AND PURPOSE An intronic polymorphism of presenilin-1 (PS-1), a gene responsible for early-onset familial Alzheimers disease, has been reported to be associated with late-onset sporadic Alzheimers disease. In a search for a genetic risk factor of sporadic cerebral amyloid angiopathy (CAA), we investigated the association of the polymorphism of PS-1 with CAA. METHODS The association between the severity of CAA and genotypes of a polymorphism in intron 8 of PS-1 was investigated in 137 autopsy cases of the elderly. RESULTS A significant decrease of PS-1 2/2 genotype frequency was associated with severe or moderate CAA. CONCLUSIONS Our results suggest that PS-1 intronic polymorphism may be associated with the severity of CAA in the elderly.

Association of neprilysin polymorphism with cerebral amyloid angiopathy

Objectives: The risk of sporadic cerebral amyloid angiopathy (CAA) may be associated with genetic polymorphisms of molecules related to anabolism or catabolism of amyloid β protein (Aβ). The authors investigated whether a polymorphism of the gene (NEP) coding for neprilysin, an enzyme catabolising Aβ, is associated with CAA. Methods: The study analysed the GT repeat polymorphism in the enhancer/promoter region of NEP and severity of CAA in 164 necropsied elderly Japanese subjects. Results: The subjects had NEP polymorphisms with 19 to 23 GT repeats and were classified into nine genotypes. CAA severity was significantly higher in the subjects with up to 40 repeats in total than those with more than 40 repeats (p=0.005). There was a significant correlation between the number of the shorter alleles (19 or 20 repeats) and CAA severity (p=0.024). In addition, there was no interaction between the NEP polymorphism and apolipoprotein E genotype. Conclusions: These results suggest the association between the NEP polymorphism and the risk of CAA. Further study using more samples from populations with different ethnic backgrounds is necessary.

No association of paraoxonase gene polymorphism with atherosclerosis or Alzheimer's disease.

Article abstract Both AD and paraoxonase (PON) have been reported to be related to lipids and atherosclerosis, suggesting that the PON gene (PON) is a possible genetic risk factor for AD. We found no association of PON polymorphism with severity of atherosclerosis, densities of AD-type, neuropathologic change, or development of AD in 47 AD and 90 nondemented patients. Our study suggests that PON polymorphism does not play a causal role in the development of atherosclerosis or AD.

Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile)

Mutations in the presenilin 1 (PS1) gene (PS1) are responsible for 30%–40% of early onset familial Alzheimers disease and over 60 mutations have been found so far. There are phenotypic variations among mutations on PS1. Three PS1 mutations, deletion of exon 9 with and without splice acceptor site mutation, and Arg278Thr have been reported to be associated with Alzheimers disease with spastic paraparesis.1 2 We report clinical and genetic features of a man who developed very early onset Alzheimers disease with spastic paraparesis, which was associated with a novel mutation of PS1, Phe237Ile. A 35 year old Japanese man had graduated from a national university and had worked as a psychiatric counsellor for a local clinic. His first neurological symptom was gait disturbance at the age of 31. At the age of 32, mild memory impairment and decreased mental activity were noted. His neurological deficits progressed gradually. On neurological evaluation at the age of 33, diffuse hyperreflexia, ataxia in all limbs, bilateral Babinskis sign, and dementia (total IQ on the WAIS-R of 75) were noted. He gave up his job at this time. At the age 34, he could not live alone because of memory deficit and cognitive dysfunction (total IQ on the WAIS-R of 59). At the age of 35, he became bedridden due to deterioration of spastic paraparesis, and presented with partial or generalised seizures a few times. His parents (66 and 63 years old) and sibling (27 years old) had no neurological deficits. There was no similar disease in other members of his family. On admission, he was alert and oriented for place, but …

α2-Macroglobulin polymorphism is not associated with AD or AD-type neuropathology in the Japanese

Background: α2-Macroglobulin (A2M) forms the complex with amyloid β-protein (Aβ) and is associated with degradation of Aβ. It has been reported that the A2M gene (A2M) exon 18 splice acceptor deletion polymorphism influences the development of AD, regardless of apolipoprotein E-ε4 (APOE-ε4) status. Objective: To determine the effect of A2M polymorphism on the development of AD and AD-type neuropathologic changes. Methods: The authors examined the A2M and APOE genotypes, the densities of the senile plaques (SPs), SPs with dystrophic neurites (NPs), and neurofibrillary tangles (NFTs) in the brains of 62 postmortem-confirmed sporadic AD and 90 nondemented patients from an autopsy series of elderly Japanese subjects. Results: There was no association of the A2M polymorphism with AD, age at onset, or duration of illness in AD. The A2M polymorphism was not associated with the SPs, NPs, or NFTs in AD or nondemented patients. The results remained insignificant, even when the A2M genotype groups were divided into subgroups by APOE-ε4 status. Conclusion: The A2M polymorphism does not affect the development of sporadic AD or formation of AD-type neuropathologic changes.

Presenilin 1 intronic polymorphism is not associated with Alzheimer type neuropathological changes or sporadic Alzheimer’s disease

BACKGROUND A genetic association between the presenilin 1 (PS-1) intronic polymorphism and sporadic Alzheimer’s disease has been a matter of controversy. Recent findings have suggested that the PS-1 polymorphism is not associated with Alzheimer’s disease or amyloid β-protein (Aβ) deposition in brains from patients with Alzheimer’s disease. OBJECTIVES To elucidate the influence of the PS-1 polymorphism on Alzheimer type neuropathological changes and the development of Alzheimer’s disease, the relation between the PS-1 polymorphism and quantitative severity of Alzheimer type neuropathological changes in the brains from patients with Alzheimer’s disease and non-demented subjects was studied. METHODS The PS-1 and apolipoprotein E (ApoE) genotypes, were examined, together with the densities of the senile plaques, senile plaques with dystrophic neurites, and neurofibrillary tangles in the brains from 36 postmortem confirmed patients with sporadic Alzheimer’s disease and 86 non-demented subjects. Association of the PS-1 polymorphism with sporadic Alzheimer’s disease and ages at onset and duration of illness in Alzheimer’s disease was also examined. RESULTS The PS-1 polymorphism was not associated with the senile plaques, senile plaques with dystrophic neurites, or neurofibrillary tangles in Alzheimer’s disease or non-demented subjects. There was no association of the PS-1 intronic polymorphism with Alzheimer’s disease, ages at onset, or durations of illness in Alzheimer’s disease. The results remained non-significant even when the PS-1 genotype groups were divided into the subgroups withdifferent ApoE ε4 status. CONCLUSIONS The PS-1 intronic polymorphism does not itself have a direct causal role in the formation of Alzheimer type neuropathological changes or in the development of sporadic Alzheimer’s disease.

Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome

Previous study has shown that the anti-Hu antibody titre of serum samples from patients with paraneoplastic encephalomyelitis/paraneoplastic sensory neuronopathy (PEM/PSN) was significantly higher than that from patients with small cell lung cancer without neurological disturbances (non-PEM/PSN). The aims of this study were (1) to identify the fine epitopes on HuD recognised by the anti-Hu antibody, (2) to determine if the pattern of epitopic reactivity differed between antibodies from patients with and without PEM/PSN, and (3) to determine if the pattern of epitopic reactivity correlated with the clinical features. Recombinant full length HuD and nine deletion fragments were constructed and immunoreacted by western blot analysis with 14 anti-Hu serum samples from eight patients with PEM/PSN and six without PEM/PSN. All anti-Hu serum samples reacted with the deletion fragments containing amino acids (aa) 90–101 or aa 171–206. Some anti-Hu samples reacted with the deletion fragments containing aa 223–234, aa 235–252, or aa 354–373. There was no difference in the pattern of epitopic reactivity between patients with and without PEM/PSN. There was no correlation between the pattern of epitopic reactivity and the clinical features. The anti-Hu antibody titre from patients with PEM/PSN was significantly higher than from patients without PEM/PSN, but there was overlap of their titre concentrations. In conclusion, aa 90–101 and aa 171–206 are the major epitopes with which all anti-Hu serum samples react, and aa 223–234, aa 235–252, and aa 354–373 are the minor epitopes with which only some anti-Hu serum samples react. The analyses suggested that the pattern of epitopic reactivity of the anti-Hu antibody on HuD was not a critical factor for the development or clinical features of PEM/PSN.