Editors' ChoiceAlzheimer’s Disease

Leaky pipes: Tau and apoE implicated in blood-brain barrier dysfunction in Alzheimer disease

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Science Translational Medicine  09 Sep 2020:
Vol. 12, Issue 560, eabe1710
DOI: 10.1126/scitranslmed.abe1710


Concentrations of tight junction proteins correlate with tau and apolipoprotein E in Alzheimer disease brain tissue independent of cerebral amyloid angiopathy.

Although Alzheimer disease (AD) is histologically defined by accumulation of amyloid plaques composed of amyloid-beta (Aβ) peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein, additional pathological changes also occur in AD including dysfunction of the blood-brain barrier (BBB). Cerebral amyloid angiopathy (CAA) occurs in the majority of AD cases and results from Aβ accumulation in arteriole walls. Although CAA is widely accepted to compromise neurovascular unit and BBB integrity, additional relationships between AD neuropathology and BBB dysfunction remain less clear. Now, Liu et al. reported that tau and apolipoprotein E (apoE) concentrations correlated with endothelial tight junction proteins independent of CAA burden.

Working with a large cohort of neuropathologically confirmed AD cases, the authors measured concentrations of the endothelial tight junction proteins CLDN5 and OCLN and found associations with tau and apoE concentrations in soluble and insoluble brain fractions. CLDN5 and OCLN concentrations were inversely correlated with apoE, total tau, and insoluble phosphorylated tau (p-tau) but directly correlated with more soluble p-tau, indicating that neuropathologic changes in tau and apoE may relate to tight junction integrity. Multivariate analysis indicated that the effects of tau and apoE concentration on tight junction protein concentration were independent of one another. Notably, CLDN5 and OCLN concentrations were not associated with CAA score, including when stratified by sex and APOE ε4 genotype, suggesting that tight junction integrity may be independent of CAA pathology. Consistent with prior links between CAA, Aβ, and apoE, and further supporting the possibility that tau pathology specifically relates to tight junction integrity, the authors found that CAA score was not associated with tau concentration but was associated with Aβ and apoE concentrations.

These data shed light on the molecular basis of BBB compromise in AD and reinforce the concept that Aβ and tau pathologies play distinct roles in neurodegeneration. As the authors note, additional work is needed to better define causative relationships between discrete molecular neuropathologic changes and BBB dysfunction in AD, and it remains to be seen whether interventions affecting tight junction physiology could modify disease course in preclinical models and in humans.

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