Endocytic pathway abnormalities precede amyloid β deposition in sporadic alzheimer's disease and down syndrome

Differential effects of APOE genotype and presenilin mutations

A. M. Cataldo, C. M. Peterhoff, Juan C Troncoso, T. Gomez-Isla, B. T. Hyman, R. A. Nixon

Research output: Contribution to journalArticle

Abstract

Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the β protein precursor (βPP), amyloid β (Aβ) peptide, and apolipoprotein E (ApoE). Early endosomes, a major site of Aβ peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes in the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as Aβ deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markers of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the ε4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenillin 1 or 2, indicating that altered endocytosis is not a consequence of Aβ deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in Aβ peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic link between EP alterations, genetic susceptibility factors, and Aβ generation and suggest differences that may be involved in Aβ generation and β amyloidogenesis in subtypes of AD.

Original languageEnglish (US)
Pages (from-to)277-286
Number of pages10
JournalAmerican Journal of Pathology
Volume157
Issue number1
StatePublished - 2000

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Presenilins
Down Syndrome
Amyloid
Alzheimer Disease
Genotype
Endosomes
Mutation
Serum Amyloid A Protein
Pyramidal Cells
Recycling
Apolipoproteins E
Endocytosis
rab4 GTP-Binding Proteins
Amyloid beta-Protein Precursor
Neocortex
Brain
Protein Transport
Genetic Predisposition to Disease
Neurodegenerative Diseases
Alleles

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Endocytic pathway abnormalities precede amyloid β deposition in sporadic alzheimer's disease and down syndrome : Differential effects of APOE genotype and presenilin mutations. / Cataldo, A. M.; Peterhoff, C. M.; Troncoso, Juan C; Gomez-Isla, T.; Hyman, B. T.; Nixon, R. A.

In: American Journal of Pathology, Vol. 157, No. 1, 2000, p. 277-286.

Research output: Contribution to journalArticle

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