The role of Aβ in the pathogenesis of Alzheimer disease is to block the perivascular drainage pathways by which interstitial fluid (ISF) and soluble metabolites are eliminated from the brain.

As cerebral arteries age, they become stiffer (arteriosclerosis) and the motive force for the perivascular drainage of ISF and soluble metabolites weakens (Schley et al., 2005; Yow and Weller, 2002). Soluble Aβ in the ISF precipitates as insoluble deposits in the perivascular drainage pathways (Weller et al., 1998), further impeding the elimination of Aβ and resulting in cerebral amyloid angiopathy (Preston et al., 2003). As more Aβ is deposited in artery walls, the more ISF drainage is impeded, and the more Aβ is deposited. As drainage of ISF is impaired, insoluble Aβ is also deposited in the extracellular spaces in grey matter, and this impedes the diffusion of ISF (Mueggler et al., 2004) and solutes as they drain towards the bulk flow perivascular drainage pathways (Abbott, 2004). With further failure of drainage of ISF, the levels of soluble metabolites rise in the extracellular...  Read more

The role of Aβ in the pathogenesis of Alzheimer disease is to block the perivascular drainage pathways by which interstitial fluid (ISF) and soluble metabolites are eliminated from the brain.

As cerebral arteries age, they become stiffer (arteriosclerosis) and the motive force for the perivascular drainage of ISF and soluble metabolites weakens (Schley et al., 2005; Yow and Weller, 2002). Soluble Aβ in the ISF precipitates as insoluble deposits in the perivascular drainage pathways (Weller et al., 1998), further impeding the elimination of Aβ and resulting in cerebral amyloid angiopathy (Preston et al., 2003). As more Aβ is deposited in artery walls, the more ISF drainage is impeded, and the more Aβ is deposited. As drainage of ISF is impaired, insoluble Aβ is also deposited in the extracellular spaces in grey matter, and this impedes the diffusion of ISF (Mueggler et al., 2004) and solutes as they drain towards the bulk flow perivascular drainage pathways (Abbott, 2004). With further failure of drainage of ISF, the levels of soluble metabolites rise in the extracellular fluid of the brain, the extracellular environment of neurons is altered, neuronal function is impaired, and cognitive decline ensues. This failure is reflected in the rise in the level of soluble Aβ in the brain that correlates so well with cognitive decline in Alzheimer disease (Lue et al., 1999; McLean et al., 1999). ISF levels rise in the white matter as observed by MRI and by the dilatation of perivascular spaces (Roher et al., 2003).

References:
Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 2004; 45: 545-552. Abstract

Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 1999; 155: 853-62. Abstract

McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 1999; 46: 860-6. Abstract

Mueggler T, Rausch M, Meyer-Luehmann M, Staufenbiel M, Jucker M, Rudin M. Restricted diffusion in the brain of transgenic mice with cerebral amyloidosis. Eur J Neurosci 2004; 20: 811-817. Abstract

Preston S D, Steart PV, Wilkinson A, Nicoll JAR, Weller RO. Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol. 2003 Apr;29(2):106-17. Abstract

Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease. Mol Med 2003; 9: 112-122. Abstract

Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 2005; Aug 19; [Epub ahead of print]. Abstract

Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol 1998; 153: 725-33. Abstract

Yow HY, Weller RO. A role for cerebrovascular disease in determining the pattern of beta amyloid deposition in Alzheimer's disease. Neuropathol Appl Neurobiol 2002; 28: 149.

View all comments by Roy O. Weller

As with many other diseases I think that AD is caused by a combination of events. The oligomers are affecting synapses, microglia are activated to produce neurotoxic substances, and intraneuronal Abeta is affecting the neuron. To me this suggests that we should be looking at combination therapies and other ways to treat AD that involve multiple aspects of the disease.

View all comments by Tim Seabrook

Alzheimer's Disease is not due to one cause. In fact any disease is a manifestation due to imbalance of cellular homeostasis, and it affects multiple pathways and networks. A disease is akin to throwing stone in a pond and ripples are the symptoms which we observe.
In Alzheimer's disease and other proteinopathies, it is neither the oligomer or the fibril which are absolute toxic or protective. Depending upon its microenvironment, either oligomer can be toxic by creating pores in the membrane or fibril can be toxic by sequestering critical proteins in the aggregates. The key imbalance here is in the amount and concentrations of the protein, be it abeta or synuclein. Once the dynamic equilibrium between monomer, dimers, and oligomers is disturbed, then cytotoxicity can be achieved through mutliple means. This is one aspect. Others like neuroinflammation and genetic make up are complicating issues.

View all comments by Neeraj Pandey