Abstract
AbstractBackgroundAlzheimer’s disease (AD) brains are characterized by extracellular amyloid‐beta (Aβ) deposition and autophagy dysregulation. Here we aimed at deepening the understanding of these brain pathologies and how they translate to the CSF using App knock‐in mice.MethodAD postmortem brain tissues and App knock‐in mouse models (AppNL‐F and AppNL‐G‐F ) were used for autophagy characterization. The cerebrospinal fluid (CSF) from App knock‐in mice was analyzed by label‐free mass spectrometry (MS) and compared with previously reported CSF MS results from patients. The expression of decorin in the mouse brains was analyzed by immunohistochemistry and western blot. The autophagy‐activating effect of decorin was measured in the mouse primary neurons.Resultp62 and LC3 II levels were increased in AppNL‐G‐Fmice similar to the marked accumulation of p62 in AD brains. Several extracellular matrix (ECM) proteins, including decorin, were significantly increased in the CSF of both AppNL‐F mice and amyloid‐positive/tau‐negative subjects with normal cognition. Decorin was decreased in parvalbumin‐positive interneurons but increased in choroideus plexus of AppNL‐Fmice, both of which correlated with Aβ pathology. Decorin‐treated mouse primary neurons exhibited lowered p62 and LC3 II levels.ConclusionAutophagy is similarly inhibited in the brains of AppNL‐G‐Fmice and AD patients. The similar increase of decorin in CSF of AppNL‐F mice and amyloid‐positive/tau‐negative subjects with normal cognition indicates a potential of decorin as an early biomarker of Aβ amyloidosis. In addition, decorin activates neuronal autophagy by increasing autophagosomal‐lysosomal degradation linking changes in ECM to autophagy.
Highlights
50 million people in the world are living with dementia and this number is estimated to triple by 2050 [1]
The results showed a pronounced p62 accumulation in both cortex (Fig. 1f) and hippocampus including dentate gyrus (DG) (Fig. 1g), CA1 (Fig. 1h), and CA3 (Fig. 1i) of Alzheimer’s disease (AD) brains, whereas no p62 accumulation was found in brains of nondemented individuals (Fig. 1a-d). p62 accumulated as large intracellular aggregations in neurons (Fig. 1f and 1g, arrow in depicted area 1, Fig. 1h, arrow in depicted area) and was identified as small round dots or outstretched structures (Fig. 1f and 1g, arrows in depicted area 2)
We further substantiate these findings by showing that p62, which is normally metabolized by autophagy, accumulates in the neurons, vessels, corpora amylacea, potential axonal beadings and apoptotic bodies of AD brains, showing that autophagy is impaired in AD brains
Summary
50 million people in the world are living with dementia and this number is estimated to triple by 2050 [1]. CAA, observed in around 40% of AD cases, consists of vascular deposits of Aβ and can affect blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) composition and potentially worsen disease progression [2, 3]. Because of the tight junction between the endothelial cells, BBB highly controls the molecular exchange between blood and brain parenchyma. It may lead to imparied Aβ clearance from brain to the peripheral circulation which may aggrevate the Aβ accumulation in the brain that further increases BBB dysfuntion [7]. During this vicious cycle, the basement membrane consisting of extracellular matrix (ECM) is affected. Whether the vascular changes are causes or consequnces of the brain pathologies remains to be fully elucidated
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