Cerebral small vessel disease-induced apolipoprotein E leakage is associated with Alzheimer disease and the accumulation of amyloid beta-protein in perivascular astrocytes

Topic: Brain proteins, microglia and lab models

Apolipoprotein E (apoE) plays a role in the pathogenesis of Alzheimer disease (AD). It is involved in the receptor-mediated cellular clearance of the amyloid beta-protein (Abeta) and in the perivascular drainage of the extracellular fluid. Microvascular changes are also associated with AD and have been discussed as a possible reason for altered perivascular drainage. To further clarify the role of apoE in the perivascular and vascular pathology in AD patients, we studied its occurrence and distribution in the perivascular space, the perivascular neuropil, and in the vessel wall of AD and control cases with and without small vessel disease (SVD). Apolipoprotein E was found in the perivascular space and in the neuropil around arteries of the basal ganglia from control and AD cases disclosing no major differences. Western blot analysis of basal ganglia tissue also revealed no significant differences pertaining to the amount of full-length and C-terminal truncated apoE in AD cases compared with controls. In contrast, Abeta occurred in apoE-positive perivascular astrocytes in AD cases but not in controls. In blood vessels, apoE and immunoglobulin G were detected within the SVD-altered vessel wall. The severity of SVD was associated with the occurrence of apoE in the vessel wall and with that of Abeta in perivascular astrocytes. These results point to an important role of apoE in the perivascular clearance of Abeta in the human brain. The occurrence of apoE and immunoglobulin G in SVD lesions and in the perivascular space suggests that the presence of SVD results in plasma-protein leakage into the brain. It is therefore tempting to speculate that apoE represents a pathogenetic link between SVD and AD.

@article{utter2008-18716559,
  author  = {Utter, S. and Tamboli, I. Y. and Walter, J. and Upadhaya, A. R. and Birkenmeier, G. and Pietrzik, C. U. and Ghebremedhin, E. and Thal, D. R.},
  title   = {{Cerebral small vessel disease-induced apolipoprotein E leakage is associated with Alzheimer disease and the accumulation of amyloid beta-protein in perivascular astrocytes}},
  journal = {Journal of neuropathology and experimental neurology},
  year    = {2008},
  doi     = {10.1097/nen.0b013e3181836a71},
  pmid    = {18716559},
  url     = {https://doi.org/10.1097/nen.0b013e3181836a71}
}

Key findings

• Microvascular changes are also associated with AD and have been discussed as a possible reason for altered perivascular drainage.
• Western blot analysis of basal ganglia tissue also revealed no significant differences pertaining to the amount of full-length and C-terminal truncated apoE in AD cases compared with controls.
• The severity of SVD was associated with the occurrence of apoE in the vessel wall and with that of Abeta in perivascular astrocytes.
• These results point to an important role of apoE in the perivascular clearance of Abeta in the human brain.
• The occurrence of apoE and immunoglobulin G in SVD lesions and in the perivascular space suggests that the presence of SVD results in plasma-protein leakage into the brain.

Why it matters

In post-mortem brain tissue, apoE and immunoglobulin G, proteins normally carried in blood, were found inside the walls of small blood vessels damaged by small vessel disease. The worse the vessel damage, the more amyloid beta turned up in nearby support cells (astrocytes); that amyloid was seen in Alzheimer's cases but not in controls. Overall apoE levels did not differ between Alzheimer's and control brains, and the authors call apoE as a link between vessel disease and Alzheimer's a speculation, not a finding. The study did not test any treatment.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1097/nen.0b013e3181836a71
• PubMed: 18716559
• Original source →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 21.

• Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families Science · 1993-08-13 · usefulness score 63/100 · Genetics
• Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice Science · 1996-10-04 · usefulness score 62/100 · Laboratory science
• The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neurology · 1991-04-01 · usefulness score 61/100 · Cognitive tests and assessment
• The Clinical Dementia Rating (CDR) Neurology · 1993-11-01 · usefulness score 59/100 · Cognitive tests and assessment
• Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein Nature · 1995-02-01 · usefulness score 59/100 · Risk genes beyond APOE
• Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Principles and Practice of Geriatric Psychiatry · 2002-04-15 · usefulness score 59/100 · Cognitive tests and assessment
• Phases of Aβ-deposition in the human brain and its relevance for the development of AD Neurology · 2002-06-25 · usefulness score 59/100 · Brain tissue and pathology
• Neuropathological stageing of Alzheimer-related changes Acta Neuropathologica · 1991-09-01 · usefulness score 58/100 · Brain tissue and pathology
• Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-03-01 · usefulness score 58/100 · Genetics
• Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse Nature · 1999-07-01 · usefulness score 57/100 · Risk genes beyond APOE
• Amyloid plaque core protein in Alzheimer disease and Down syndrome Proceedings of the National Academy of Sciences of the United States of America · 1985-06-01 · usefulness score 56/100 · Down syndrome and Alzheimer's
• A New Clinical Scale for the Staging of Dementia The British Journal of Psychiatry · 1982-06-01 · usefulness score 54/100 · Cognitive tests and assessment

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