The global prevalence of
Alzheimer’s Disease (AD) has increased significantly and has a huge economic
impact. It most common form of dementia, is now representing one of the largest
global healthcare challenges and estimated that approximate 25 million people
worldwide suffer from this dreadful condition (Mayeux and Sano, 1999).
Although, the etiology of Alzheimer’s disease and its pathophysiology is still
unclear. Accumulation of amyloid-beta (A?) in the brain is hypothesized to
trigger pathogenic cascades that eventually lead to AD. Extracellular deposits
of A? peptide (e.g. in senile plaques) and intraneuronal accumulations of tau
protein (e.g. in neurofibrillary tangles) are the main histopathological
features of AD. A? deposits are present in the cortical gray matter, years
before the onset of dementia.AD is also characterized by chronic brain
inflammation and the action free radicals on brain tissue has been investigated
extensively and the problem of oxidative is now considered to be one important
factor in the progression of cognitive impairment (a hallmark of the disease).
From the perspective of
oxidative stress and AD the blood-brain barrier (BBB) plays a significant role.
BBB is a highly specialized endothelial cell membrane that lines the cerebral
micro-vessels (that make up about 95% of the total surface area) that
represents the interface between brain (neural cells) and circulating immune cells
(such as leukocytes etc). Studies show that the BBB plays a critical role in the
manifestation and progression of chronic inflammation during earlier stages of AD.
The BBB is part of the neurovascular unit (NVU), which
is comprised of glial cell clusters, neurons and pericytes.
During the onset of AD, it is
observed that there is a BBB dysfunction and this manifests as lower A? plaque clearance
rates, impaired endothelial transport, changes in pericyte functions, and
decreased tight junction (TJ) integrity, activation of glial cells and neuro-inflammation
through the recruitment of leukocytes in the brain. As AD progresses, several
components of the neurovascular unit undergo functional/morphological changes
and become dysfunctional, this leads to nervous tissue detrition and cognitive deficits.
In experiments using transgenic animal which had AD-like pathology, it has been
shown that circulating leukocytes can actually migrate through the endothelial
cells and is known to have strong interactions with the NVU components and
potentially affecting their functionality and also their structural integrity.
Various degrees of cognitive impairment
(memory loss being very common) were reported to be associated with cholinergic
neuronal loss in dementia cases (Bondy, 1995). Cholinergic modulation is vital function
required for short-term memory process and the cholinergic dysfunction can play
a crucial role for short term memory deficits (Galizia, 1984). Recently, a plethora
of new evidence has suggested that the prime candidate responsible for
producing the neuronal changes mediating these cognitive deficits appeared to be
free radicals and oxidative stress. Additionally, some studies have also
suggested that deficits in cholinergic neurotransmitter systems and increased
levels of free radicals and proinflammatory cytokines might be involved in AD