NACP/α-synuclein, NAC, and β-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation

A clinicopathological study of two autopsy cases

O. Yokota, Seishi Terada, Hideki Ishizu, Hiroshi Ujike, Takeshi Ishihara, Hanae Nakashima, Minoru Yasuda, Yoshihiro Kitamura, Kenji Uéda, Fréderic Checler, Shigetoshi Kuroda

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Approximately 60% of familial and sporadic Alzheimer's disease (AD) cases manifest Lewy bodies (LBs), of which a major component is α-synuclein. Although the pathogenic role of α-synuclein in AD remains unclear, LB formation might be associated with pathological β-amyloid (Aβ) overproduction. Here, we present the clinical and pathological characteristics of two affected family members from a pedigree with the E184D mutation of presenilin-1. One case presented with typical clinical features of AD, but the other case also developed clinical characteristics of dementia with Lewy bodies (DLB), including visual hallucinations, delusions, and parkinsonism. In both cases, neuropathological examination revealed numerous neurofibrillary tangles and severe Aβ deposition in senile plaques and amyloid angiopathy, in which Aβ42 rather than Aβ40 was predominant. Furthermore, remarkable α-synuclein pathology, including LBs and the accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the case that presented with the symptoms of DLB. These findings suggest that (1) LB pathology can influence the clinical features of familial AD, (2) the E184D mutation of presenilin-1 may be associated with the LB formation through Aβ overproduction, although the process of LB formation is strongly affected by other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a common pathophysiological background inducing NAC accumulation in neuritic plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is modulated by the abnormally aggregated tau protein.

Original languageEnglish
Pages (from-to)637-648
Number of pages12
JournalActa Neuropathologica
Volume104
Issue number6
Publication statusPublished - 2002

Fingerprint

Synucleins
Presenilin-1
Lewy Bodies
Amyloid
Autopsy
Alzheimer Disease
Pathology
Mutation
Amyloid Plaques
Lewy Body Disease
Astrocytes
tau Proteins
Neurofibrillary Tangles
Delusions
Hallucinations
Parkinsonian Disorders
Pedigree
Neurodegenerative Diseases

Keywords

  • α-synuclein
  • β-Amyloid
  • Astrocyte
  • Familial Alzheimer's disease
  • Non-Aβ component of Alzheimer's disease amyloid

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

NACP/α-synuclein, NAC, and β-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation : A clinicopathological study of two autopsy cases. / Yokota, O.; Terada, Seishi; Ishizu, Hideki; Ujike, Hiroshi; Ishihara, Takeshi; Nakashima, Hanae; Yasuda, Minoru; Kitamura, Yoshihiro; Uéda, Kenji; Checler, Fréderic; Kuroda, Shigetoshi.

In: Acta Neuropathologica, Vol. 104, No. 6, 2002, p. 637-648.

Research output: Contribution to journalArticle

Yokota, O, Terada, S, Ishizu, H, Ujike, H, Ishihara, T, Nakashima, H, Yasuda, M, Kitamura, Y, Uéda, K, Checler, F & Kuroda, S 2002, 'NACP/α-synuclein, NAC, and β-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: A clinicopathological study of two autopsy cases', Acta Neuropathologica, vol. 104, no. 6, pp. 637-648.
Yokota, O. ; Terada, Seishi ; Ishizu, Hideki ; Ujike, Hiroshi ; Ishihara, Takeshi ; Nakashima, Hanae ; Yasuda, Minoru ; Kitamura, Yoshihiro ; Uéda, Kenji ; Checler, Fréderic ; Kuroda, Shigetoshi. / NACP/α-synuclein, NAC, and β-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation : A clinicopathological study of two autopsy cases. In: Acta Neuropathologica. 2002 ; Vol. 104, No. 6. pp. 637-648.
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abstract = "Approximately 60{\%} of familial and sporadic Alzheimer's disease (AD) cases manifest Lewy bodies (LBs), of which a major component is α-synuclein. Although the pathogenic role of α-synuclein in AD remains unclear, LB formation might be associated with pathological β-amyloid (Aβ) overproduction. Here, we present the clinical and pathological characteristics of two affected family members from a pedigree with the E184D mutation of presenilin-1. One case presented with typical clinical features of AD, but the other case also developed clinical characteristics of dementia with Lewy bodies (DLB), including visual hallucinations, delusions, and parkinsonism. In both cases, neuropathological examination revealed numerous neurofibrillary tangles and severe Aβ deposition in senile plaques and amyloid angiopathy, in which Aβ42 rather than Aβ40 was predominant. Furthermore, remarkable α-synuclein pathology, including LBs and the accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the case that presented with the symptoms of DLB. These findings suggest that (1) LB pathology can influence the clinical features of familial AD, (2) the E184D mutation of presenilin-1 may be associated with the LB formation through Aβ overproduction, although the process of LB formation is strongly affected by other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a common pathophysiological background inducing NAC accumulation in neuritic plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is modulated by the abnormally aggregated tau protein.",
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AU - Terada, Seishi

AU - Ishizu, Hideki

AU - Ujike, Hiroshi

AU - Ishihara, Takeshi

AU - Nakashima, Hanae

AU - Yasuda, Minoru

AU - Kitamura, Yoshihiro

AU - Uéda, Kenji

AU - Checler, Fréderic

AU - Kuroda, Shigetoshi

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