Endothelial Dysfunction and Chronic Low-Grade Inflammation as Potential Therapeutic Targets in Dementia Disorders
Pp. 41-82 (42)
Asija Zaciragic, Nesina Avdagic, Nermina Babic, Amela Devisevic, Amina Valjevac, Almir Fajkic, Jasminko Huskic, Almira Hadzovic-Dzuvo and Orhan Lepara
The inability of drugs based on the amyloid-clearing strategies to provide
benefits for Alzheimer’s disease (AD) patients has led to widely accepted notion that
the paradigm in dementia research should be broaden beyond amyloid deposition and
clearance. In recent years significant overlap between cardio-metabolic risk factors and
cognitive decline has been reported. Consistent with these observations, the importance
of endothelial dysfunction in the development of AD has been highlighted. According
to newly proposed “vascular hypothesis” for AD development, vascular risk factors
lead to blood–brain barrier (BBB) dysfunction and a reduction in the cerebral blood
flow. These two detrimental vascular changes result in the reduction of amyloid-β
clearance as well as in its increased production leading to consequent amyloid- β
accumulation. The increase in amyloid-β leads to neuronal dysfunction and injury
causing cognitive dysfunction and neurodegeneration with consequent dementia.
Furthermore, a growing body of evidence also suggest that the impaired structure and
function of cerebral blood vessels and cells in AD patients is mediated by vascular
oxidative stress as well as by chronic low-grade inflammation. The importance of
inflammatory changes in many age-related diseases including dementia has led to coining and use of the term “inflammaging” to indicate that ageing is accompanied by a
low-grade chronic up-regulation of certain pro-inflammatory responses.
The aim of this chapter is to provide a comprehensive insight into currently available
evidence on molecular pathways and players implicated in the above mechanisms.
Furthermore, chapter summarizes findings from ongoing clinical trials and results from
studies using novel pharmacological therapeutics targeting endothelial dysfunction and
chronic low-grade inflammation as pathophysiological events that contribute to the
onset and development of dementia disorders.
Department of Human Physiology, Medical Faculty University of Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina.