Pathogenetic Role of Amyloid Precursor Protein in Alzheimer’s Disease: The Internal Disintegration Hypothesis Revisited

Yoshikawa, Kazuaki

doi:https://doi.org/10.18910/102763

Pathogenetic Role of Amyloid Precursor Protein in Alzheimer’s Disease: The Internal Disintegration Hypothesis Revisited

Yoshikawa, Kazuaki

2025, 1-23

アクセス数:64件（2026-02-13 14:55 集計）

固定URL: https://doi.org/10.18910/102763

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APP Review Yoshikawa	pdf	なし	11.4 MB	50	2025.10.10

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タイトル	Pathogenetic Role of Amyloid Precursor Protein in Alzheimer’s Disease: The Internal Disintegration Hypothesis Revisited
著者	NRID 1000030094452 1000030094452 researchmap permalink read0185192 read0185192 Scopus Author ID 55487316500 55487316500 著者名 Yoshikawa, Kazuaki
キーワード等	APP
	amyloid plaque
	amyloidogenic fragment
	neurodegeneration
	apoptosis
	caspase-3
	calpain
	lysosome
	programmed cell death
	Alzheimer’s disease
内容	Review
抄録	Alzheimer’s disease is characterized by massive neuronal degeneration and extracellular amyloid deposition in the brain. Although there have been numerous studies exploring these pathological hallmarks, a causal relation between the two events remains elusive. The most prevailing idea is that the extracellular deposition of amyloid, which results from the polymerization of amyloid-b protein generated by abnormal processing of amyloid precursor protein (APP), leads to neuronal degeneration ‘from outside’ (the amyloid cascade hypothesis, 1992). The author of this review proposed an alternative hypothesis based on the analyses of APP-overexpressing cell models (the internal disintegration hypothesis, 1995). This hypothesis is that intraneuronal accumulations of APP and its amyloidogenic fragments generated in the lysosomes contribute primarily to neuronal death ‘from inside’, implying that the extracellular amyloid deposition is an accompanying event. Further studies have shown that caspase-3, a key apoptosis-executioner protease, is activated in APP-overexpressing degenerating neurons where the intracellular accumulation of APP leads to a sequential activation of the Ca2+-activated protease calpain and caspase-3. Moreover, APP-induced apoptosis is likely to operate in nascent neurons during the early period of development. In this review, the author revisits the hypothesis and discusses that APP plays a neuroprotective role but induces neurodegeneration when its accumulation reaches a critical level to trigger the apoptotic pathway. This hypothesis has been corroborated by multiple lines of evidence in studies on mutant APP transgenic mice and neuropathological findings in Alzheimer’s disease.
出版者	Yoshikawa, Kazuaki
ページ	1-23
刊行年月	2025-09-19
言語	英語
ハンドルURL	https://hdl.handle.net/11094/102763
DOI	https://doi.org/10.18910/102763
アクセス権	open access
出版タイプ	Version of Record
カテゴリ	研究報告書 Research Paper

資源タイプ	研究報告書
ローカル資源タイプ	研究報告書
DCMI資源タイプ	text
DC.title	Pathogenetic Role of Amyloid Precursor Protein in Alzheimer’s Disease: The Internal Disintegration Hypothesis Revisited
DC.creator	Yoshikawa, Kazuaki
DC.publisher	Yoshikawa, Kazuaki
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-09-19
DC.subject	APP
	amyloid plaque
	amyloidogenic fragment
	neurodegeneration
	apoptosis
	caspase-3
	calpain
	lysosome
	programmed cell death
	Alzheimer’s disease
DC.description	Review
DCTERMS.abstract	Alzheimer’s disease is characterized by massive neuronal degeneration and extracellular amyloid deposition in the brain. Although there have been numerous studies exploring these pathological hallmarks, a causal relation between the two events remains elusive. The most prevailing idea is that the extracellular deposition of amyloid, which results from the polymerization of amyloid-b protein generated by abnormal processing of amyloid precursor protein (APP), leads to neuronal degeneration ‘from outside’ (the amyloid cascade hypothesis, 1992). The author of this review proposed an alternative hypothesis based on the analyses of APP-overexpressing cell models (the internal disintegration hypothesis, 1995). This hypothesis is that intraneuronal accumulations of APP and its amyloidogenic fragments generated in the lysosomes contribute primarily to neuronal death ‘from inside’, implying that the extracellular amyloid deposition is an accompanying event. Further studies have shown that caspase-3, a key apoptosis-executioner protease, is activated in APP-overexpressing degenerating neurons where the intracellular accumulation of APP leads to a sequential activation of the Ca2+-activated protease calpain and caspase-3. Moreover, APP-induced apoptosis is likely to operate in nascent neurons during the early period of development. In this review, the author revisits the hypothesis and discusses that APP plays a neuroprotective role but induces neurodegeneration when its accumulation reaches a critical level to trigger the apoptotic pathway. This hypothesis has been corroborated by multiple lines of evidence in studies on mutant APP transgenic mice and neuropathological findings in Alzheimer’s disease.
DC.identifier	10.18910/102763
DC.format	102763
citation_title	Pathogenetic Role of Amyloid Precursor Protein in Alzheimer’s Disease: The Internal Disintegration Hypothesis Revisited
citation_author	Yoshikawa, Kazuaki
citation_publisher	Yoshikawa, Kazuaki
citation_language	英語
citation_date	2025-09-19
citation_firstpage	1
citation_lastpage	23
citation_public_url	https://hdl.handle.net/11094/102763
citation_doi_detail	10.18910/102763
citation_doi	https://doi.org/10.18910/102763

Pathogenetic Role of Amyloid Precursor Protein in Alzheimer’s Disease: The Internal Disintegration Hypothesis Revisited

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