More on Declining Fluid Drainage and Amyloid-β Accumulation

Amyloid-β is a species of misfolded protein that forms solid clumps in the brain. Its accumulation and related processes are associated with the progression of Alzheimer's disease. This isn't a slow progress of gathering waste, however, as levels of amyloid-β are quite dynamic. It is more the slow deterioration in mechanisms associated with ongoing clearance. So in addition to the great level of interest in developing treatments to clear amyloid-β from brain tissues, there is also much ongoing research relating to understanding why amyloid presence increases with age. One contribution is possibly a decline in the function of various drainage paths that occurs for much the same reasons as the general decline in blood vessel function throughout the body:

In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain.

CSF-ISF exchange and interstitial solute clearance was evaluated in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was also evaluated. Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.



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