Alzheimer’s Disease Basic Scientific Article
Fibrin deposition accelerates neurovascular damage and
neuroinflammation in mouse models of Alzheimer’s disease.
Alzheimer’s disease (AD) is characterized by
abnormal senile plaques and neurofibrillary tangle formations. Amyloid-β peptide (AB) and precursor protein
(AβPP) are the major components of these senile plaques. Aβ is thought to be a major contributor to
the neurodegenerative process, acting either through neurotoxic mechanisms or
local inflammatory processes. Interestingly
one of the early hallmarks of AD is abnormal cerebral vasculature. Neurovascular damage can allow fibrinogen
access to the CNS. Fibrinogen,
classically known for its role in the clotting cascade, cannot normally cross
the BBB. Fibrin is found in the brains
of AD patients, but the pathological significance is unknown. Fibrin accumulation can be reduced
genetically or pharmalogically.
The aim of the experiment is to measure BBB
permeability and fibrin deposition in three mouse models of AD. Their results demonstrate BBB damage and the
presence of fibrin in the brain of AD mice. Furthermore the tPA/plasmin
system, which likely aids in the clearance of Aβ, is down regulated in AD in
accord with reductions in other naturally occurring Aβ-degrading proteases. Also modulation of fibrin levels affects the
pathology of AD mice, reducing fibrinolysis, thereby increases fibrin deposits,
worsening the pathology, whereas fibrinogen depletion attenuates microgliosis and
neurovascular damage. Decreased clearance
of fibrin is also thought to contribute to the progression of Aβ
pathology. The initial insult to the
microvasculature likely arises from increased Aβ levels. Fibrinogen binding elicits activation of
NF-KB, caused increased expression of cytokine genes. Thus fibrin may be an upstream effector of neuroinflammation . Also
fibrin-induced microgliosis could be toxic to endothelial cells. Fibrin along with the mechanisms involved in
its clearance, may present novel therapeutic targets for slowing the
progression of AD.
The author’s utilized pharmacological methods
to examine fibrin’s role, namely from platelets, in AD mouse models. The aim was to reduce protein sources, which
are linked to senile plaques, in order to prevent or lessen AD. The data does suggest that this therapy is
an effective way of modulating AD in mouse models. However if this line of therapy was employed in human subjects
significant side effects could result.
Humans are far more sensitive to reductions in platelet levels compared
to mice. If human platelet levels were
reduced to those of the mice in these studies minor injuries could become
life-threatening situations.
Source: Justin Paul, Sidney Strickland, and Jerry P.
Melchor: Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer ’ s disease, Laboratory of Neurobiology and Genetics, The
Rockefeller University, New York, NY 10065.
