A study, reported last year here, in mice shows how a breakdown of the
brain's blood vessels may amplify or cause problems associated with Alzheimer's
disease. The results published in Nature Communications suggest that blood
vessel cells called pericytes may provide novel targets for treatments and
diagnoses.
This
study helps show how the brain's vascular system may contribute to the
development of Alzheimer's disease," said study leader Berislav V.
Zlokovic, M.D. Ph.D., director of the Zilkha Neurogenetic Institute at the Keck
School of Medicine of the University of Southern California, Los Angeles. The
study was co-funded by the National Institute of Neurological Diseases and
Stroke (NINDS) and the National Institute on Aging (NIA), parts of the National
Institutes of Health.
Alzheimer's
disease is the leading cause of dementia. It is an age-related disease that
gradually erodes a person's memory, thinking, and ability to perform everyday
tasks. Brains from Alzheimer's patients typically have abnormally high levels
of plaques made up of accumulations of beta-amyloid protein next to brain
cells, tau protein that clumps together to form neurofibrillary tangles inside
neurons, and extensive neuron loss.
Vascular
dementias, the second leading cause of dementia, are a diverse group of brain
disorders caused by a range of blood vessel problems. Brains from Alzheimer's
patients often show evidence of vascular disease, including ischemic stroke,
small hemorrhages, and diffuse white matter disease, plus a buildup of
beta-amyloid protein in vessel walls. Furthermore, previous studies suggest
that APOE4, a genetic risk factor for Alzheimer's disease, is linked to brain
blood vessel health and integrity.
"This
study may provide a better understanding of the overlap between Alzheimer's
disease and vascular dementia," said Roderick Corriveau, Ph.D., a program
director at NINDS.
One
hypothesis about Alzheimer's disease states that increases in beta-amyloid lead
to nerve cell damage in the brain. This is supported by genetic studies that
link familial forms of the disease to mutations in amyloid precursor protein
(APP), the larger protein from which plaque-forming beta-amyloid molecules are
derived. Nonetheless, previous studies on mice showed that increased
beta-amyloid levels reproduce some of the problems associated with Alzheimer's.
The animals have memory problems, beta-amyloid plaques in the brain and
vascular damage but none of the neurofibrillary tangles and neuron loss that
are hallmarks of the disease.
In
this study, the researchers show that pericytes may be a key to whether
increased beta-amyloid leads to tangles and neuron loss.
Pericytes
are cells that surround the outside of blood vessels. Many are found in a brain
plumbing system called the blood-brain barrier. It is a network that
exquisitely controls the movement of cells and molecules between the blood and
the interstitial fluid that surrounds the brain's nerve cells. Pericytes work
with other blood-brain barrier cells to transport nutrients and waste molecules
between the blood and the interstitial brain fluid.
To
study how pericytes influence Alzheimer's disease, Dr. Zlokovic and his
colleagues crossbred mice genetically engineered to have a form of APP linked
to familial Alzheimer's with ones that have reduced levels of platelet-derived
growth factor beta receptor (PDGFR-beta), a protein known to control pericyte
growth and survival. Previous studies showed that PDGFR-beta mutant mice have
fewer pericytes than normal, decreased brain blood flow, and damage to the
blood-brain barrier.
"Pericytes
act like the gatekeepers of the blood-brain barrier," said Dr. Zlokovic.
Both
the APP and PDGFR-beta mutant mice had problems with learning and memory.
Crossbreeding the mice slightly enhanced these problems. The mice also had
increased beta-amyloid plaque deposition near brain cells and along brain blood
vessels. Surprisingly, the brains of the crossbred mice had enhanced neuronal
cell death and extensive neurofibrillary tangles in the hippocampus and
cerebral cortex, regions that are typically affected during Alzheimer's.
"Our
results suggest that damage to the vascular system may be a critical step in
the development of full-blown Alzheimer's disease pathology," said Dr.
Zlokovic.
Further
experiments suggested that pericytes may transport beta-amyloid across the
blood-brain barrier into the blood and showed that crossbreeding the mice
slowed the rate at which beta-amyloid was cleared away from nerve cells in the
brain.
Next,
the researchers addressed how beta-amyloid may affect the vascular system. The
crossbred mutants had more pericyte death and more damage to the blood-brain
barrier than the PDGFR-beta mutant mice, suggesting beta-amyloid may enhance
vascular damage. The investigators also confirmed previous findings showing
that beta-amyloid accumulation leads to pericyte death.
Dr.
Zlokovic and his colleagues concluded that their results support a two-hit
vascular hypothesis of Alzheimer's. The hypothesis states that the toxic
effects of increased beta-amyloid deposition on pericytes in aged blood vessels
leads to a breakdown of the blood-brain barrier and a reduced ability to clear
amyloid from the brain. In turn, the progressive accumulation of beta-amyloid
in the brain and death of pericytes may become a damaging feedback loop that
causes dementia. If true, then pericytes and other blood-brain barrier cells
may be new therapeutic targets for treating Alzheimer's disease.
More
information: Sagare et al. "Pericyte loss influences Alzheimer-like
neurodegeneration in mice" Nat. Commun., December 13, 2013. DOI:
10.1038/ncomms3932
Journal
reference: Nature Communications Provided
by National Institutes of Health
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