Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations.
Journal: 2000/August - American Journal of Pathology
ISSN: 0002-9440
PUBMED: 10880397
Abstract:
Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (betaPP), amyloid beta (Abeta) peptide, and apolipoprotein E (ApoE). Early endosomes, a major site of Abeta 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 Abeta 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 epsilon4 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 presenilin 1 or 2, indicating that altered endocytosis is not a consequence of Abeta 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 Abeta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic link between EP alterations, genetic susceptibility factors, and Abeta generation and suggest differences that may be involved in Abeta generation and beta amyloidogenesis in subtypes of AD.
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Am J Pathol 157(1): 277-286

Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome

From the Nathan S. Kline Institute for Psychiatric Research,*
Orangeburg, New York; the New York University School of Medicine,
New York, New York; the Department of Pathology (Neuropathology) and Neurology,
The Johns Hopkins University School of Medicine, Baltimore, Maryland; and the Department of Neurology,§
Massachusetts General Hospital, Boston, Massachusetts
Accepted 2000 Mar 14.

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 presenilin 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.

Abstract

In neurons, the endocytic pathway (EP) internalizes and processes extracellular nutrients and trophic factors; recycles, modifies, and degrades receptors and other integral membrane proteins after neurotransmitter release; and directs information to intracellular biosynthetic pathways. Endocytosis enables neurons to modify or degrade molecules from the cell surface into intracellular compartments by a series of fusion and budding events. This complex of compartments known as the central vacuolar system consists of early and late endosomes and lysosomes that have different capabilities for proteolytic processing. Most resident acid hydrolases in central vacuolar system compartments are processed in the Golgi apparatus and subsequently trafficked to acidic organelles under the regulation of two species (46 kd and 215 kd) of mannose 6-phosphate receptors. The turnover of internalized proteins and lipids was originally thought to be limited to lysosomes, but it is now known that some acid proteases are present in early endosomes and are capable of modifying endocytosed materials.

Early endosomes are the first major sorting station on the endocytic pathway and the site of internalization and initial processing of proteins relevant to AD pathogenesis like the β protein precursor (βPP) and apolipoprotein E (ApoE). Early endosomes are also a major site of amyloid β (Aβ) peptide production in normal cells and mediate the cellular uptake of Aβ and soluble iPP. Numerous studies have implicated both the secretory pathway, specifically the endoplasmic reticulum 1-4 and Golgi apparatus 5-8 and EP 9-12 in βPP processing and the production of Aβ 1–40, Aβ 1–42, or both.

In previous studies of sporadic Alzheimer’s disease (SAD) brain, we found that the volumes of neuronal early endosomes were, on average, threefold larger than normal, which is a morphological change known to be associated with increased EP activity. 13,14 In addition, levels of immunoreactive cathepsins D and B in both their pro- and mature forms were elevated within enlarged endosomes, 15 coinciding in these neurons with increases of cation-dependent mannose 6-phosphate receptors, which mediates the delivery of acid hydrolases, including cathepsins, to early endosomes. One of the cathepsins mistrafficked in these models, cathepsin D, has been shown to have βPP β/γ secretase activity toward model peptides, recombinant βPP and the C-100 fragment of βPP. 16-19 Our previous studies have demonstrated that lysosomal system (LS) activation evidenced by an increase in gene expression and accumulation of lysosomes is an early and distinctive response of neurons in SAD and Down syndrome (DS). 20-22 Neurons exhibiting overt atrophy or neurofibrillary change display robust accumulation of hydrolase-positive lysosomes and lipofuscin granules which are then released into the parenchyma after cell lysis. These compartments containing a battery of enzymatically competent hydrolases, persist in the extracellular space in association with deposits of Aβ in both senile and diffuse plaques. 21-23 By immunocytochemistry, we have found that in cases of familial Alzheimer’s disease (FAD) linked to presenilin (PS) 1 and PS2 mutations, LS activation was greater in pyramidal neurons in cortical laminae III and V than in SAD. 24 Neuronal populations that are less vulnerable in SAD, such as those in cortical lamina II and IV of the prefrontal cortex, showed marked LS up-regulation in PS-FAD. Like SAD, senile plaques in PS-FAD brains displayed intense hydrolase immunoreactivity. 24 Compared with SAD, PS-FAD promotes an earlier and excessive deposition of Aβ 1–42. 25,26 The enhanced LS response seen in PS-FAD is consistent with in vitro studies showing that Aβ 1–42 accumulates in late endosomes and lysosomes. 27

In the present study, we further characterized the EP in SAD using antibody probes to molecules known to regulate specific aspects of the endocytic process. Moreover, we investigated the onset of EP dysfunction in the brains of nondemented individuals exhibiting the earliest Alzheimer-like pathological changes restricted to the entorhinal cortex and hippocampus. The analysis was extended to earlier stages of pathogenesis in brains from fetuses and juveniles with DS (trisomy 21), a form of mental retardation invariably associated with the development of AD neuropathology after age 40. 28 Finally, we analyzed the influence of normal aging, APOE genotype, and PS mutations on endosome morphology in relation to the evolution of AD neuropathology. Our results show that early endosomal abnormalities are the earliest neuropathological alteration yet to be identified in SAD. Their appearance is greatly accelerated by triplication of the distal half of the long arm of chromosome 21 (DS). Inheritance of the APOE ε4 allele, which substantially increases the risk for developing AD and promotes earlier disease onset 29 also promoted earlier appearance of endosome enlargement. Finally, in a variety of neurodegenerative diseases and, significantly, in severely affected individuals with FAD linked to four different mutations of PS1 and the Asn141-Ile mutation of PS2, endosomes were normal in size. These observations indicate that the neuronal endosomal response seen in AD is highly disease-specific and does not seem to be a secondary effect of Aβ deposition. An understanding of the origins and effects of this abnormal endocytic response should provide important insight into pathogenic mechanisms in sporadic AD, the most common and least well understood form of AD.

Acknowledgments

We thank Lucy Morales for secretarial assistance in preparing the manuscript for publication.

Acknowledgments

Footnotes

Address reprint requests to Anne M. Cataldo, Ph.D., Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962. E-mail: .gro.hmfr.ikn@odlatac

Supported in part by National Institutes of Health grants AG 10916 (to R. A. N.) and AG14762 (to A. M. C.).

Footnotes

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