Serum Protein Leakage in Alzheimer's Disease Revisited

Abstract

Leakage of serum proteins into the brain parenchyma has been repeatedly used as evidence of blood-brain barrier (BBB) damage in experimental and human studies. However, there is no consensus in the literature concerning this phenomenon in Alzheimer's disease (AD). We have examined this question by comparing frontal lobe sections in seven groups of patients: Multi-infarct dementia (n = 6), AD with (n = 10) and without (n = 10) infarcts, age-matched controls with (n = 10) and without (n = 10) infarcts, controls with neurodegenerative diseases other than AD, and young controls (n = 10). An additional series compared prospectively followed patients with a diagnosis of either multi-infarct dementia (n = 5) or AD (n = 4). Albumin was detected in white-matter astrocytes in all cases, without significant variation in intensity. In addition, diverse combinations of neurons, astrocytes, and (in AD patients) senile plaques were present in the cerebral cortex in an inconsistent manner. Semiquantitative analysis showed no statistically significant differences among groups. Anti-IgG labeled astrocytes in infarcts only. Complement C3c component was detected in rare amyloid plaques in a minority (15%) of AD cases. Selective labeling of AD-specific lesions in a patchy manner was observed for serum amyloid P. We conclude that there is no immunohistochemical evidence of alteration of the BBB in Alzheimer's disease with or without vascular factors or in old age. Serum amyloid P binds avidly to AD lesions, but our findings are consistent with leakage through the BBB during the agonal or immediate postmortem period. Finally, no specific pattern of abnormality in the BBB was detected in multi-infarct dementia.

Cyclooxygenase‐2‐positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood–brain barrier

“…Power and coworkers [54] observed diffuse myelin pallor in the subcortical white matter, which they attributed to the damage of BBB but not to demyelination. These neuropathological findings are in agreement with previous biochemical studies of the cerebrospinal fluid, which suggested only weak and inconstant evidence of a leak across the blood-CSF barrier in AD [56][57][58][59][60][61][62]. Tight junction damage in AD is more discrete compared with tight junction damage in HIVE, as shown by less ZO-1 disruption and fibrinogen leakage [6,7].…”

Increased blood–brain barrier permeability with thymidine phosphorylase deficiency

“…Whereas there is postmortem leakage of albumin into the intercellular space, the intracellular immunoreactivity in astrocytes and neurons reflects antemortem BBB dysfunction. 15 We found a statistically significant difference in the number of albumin-positive cells between MNGIE patients and healthy control subjects, and similar results to those in a patient we studied with with PRLE. 16 Is the BBB dysfunction a primary or secondary phenomenon in MNGIE?…”

Microangiopathy in the cerebellum of patients with mitochondrial DNA disease

“…Blood–brain barrier disruption might present an additional strain on neighbouring neurons and glial cells since they appear to actively uptake plasma protein components to remove them from the brain microenvironment (Matz et al ., 2001). It has been suggested that uptake by neurons and astrocytes may merely represent post-mortem changes in blood–brain barrier permeability (Mori et al ., 1991; Munoz et al ., 1997); however, plasma protein extravasation was much higher in patient tissues compared to control indicating that changes in localization of fibrinogen and IgG are true pathological alterations. In fact, a recent study links fibrinogen leakage into the brain parenchyma with neuronal damage in Alzheimer’s disease (Cortes-Canteli et al ., 2010).…”