AN EXPERIMENTAL MODEL FOR THE ALZHEIMER PHENOTYPE OF
COGNITIVE DEFICITS
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1
Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Ischemic and Neurodegenerative Brain Research, Department of Neurodegenerative Disorders, Poland
-
2
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Molecular Neurobiology, Department of Molecular and Cellular Neurobiology, Poland
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3
Lublin Medical University, Department of Orthopedics and Rehabilitation, Poland
Alzheimer’s disease is an incurable neurodegenerative disease and the most common cause of dementia in adults. In clinical study it was estimated that Alzheimer’s disease accounted for 75% of all dementias. The clinical features include progressive and relentless in memory and other cognitive spheres such as executive dysfunction, language problems, visual perceptual difficulties, apraxia and agnosia, as well as neuropsychiatric disturbances. During the moderate to severe stage of Alzheimer’s disease, major decline in memory, function and behavior become evident. In turn, patients at this stage often become an enormous burden on caregivers, as well as a huge strain on the cost of health care for the society. Any improvements in patient function and relief from caregiver burden will significantly affect the health and well-being of both the patients and their family. The neuropathological hallmarks of Alzheimer’s disease are the presence of neuritic plaques, neurofibrillary tangles, neuronal loss and atrophy of brain. A number of experimental and clinical molecular studies suggest that following ischemia β-amyloid peptide from amyloid precursor protein is the pivotal initiation step in Alzheimer’s disease pathogenesis, and is responsible for neuronal degeneration and blood-brain barrier insufficiency (Pluta 2007a see for references). Based on the rival ischemic hypothesis, the formation of ischemic β-amyloid peptide can interfere directly with memory formation, and trigger a host of secondary processes including hyperphosphorylation, neurofibrillary tangles formation, excitotoxicity, oxidative stress, inflammation, demyelination and finally neuronal death (Figure 1, Pluta et al. 2009). While the accumulation of amyloid is felt to be the main inciting factor of Alzheimer’s disease pathogenesis, the correlation between the formation and disposition of neuritic plaques and the clinical presentation of cognitive impairment remains unclear. Based on last data brain ischemia has a critical role in Alzheimer’s disease (Pluta et al. 2009). Recent experimental and clinical data suggest that neurovascular insufficiency may precede cognitive decline and onset of degenerative changes in Alzheimer’s disease. Brain ischemia and impaired amyloid peptide clearance across the ischemic blood-brain barrier (Pluta 2007b) may contribute to the onset and progression of Alzheimer type dementia (Figure 1). Brain ischemia negatively affects the synthesis of proteins required for memory and learning, and may eventually lead to amyloid plaques development and to neuritic injury and neuronal death (Pluta et al. 2010). Impaired clearance of β-amyloid peptide from the brain tissue by the cells of the blood-brain barrier unit may lead to its accumulation on blood neurovessels and in brain parenchyma. The accumulation of β-amyloid peptide on the brain blood vessels, known as cerebral amyloid angiopathy (Figure 1), is associated with cognitive decline and is one of the hallmarks of Alzheimer’s disease pathology (Pluta 2007a see for references). Cerebral amyloid angiopathy can severely disrupt the integrity of the neurovessel wall resulting in micro or macro hemorrhages that exacerbates neurodegenerative process and increases inflammatory response. Here, we review the role of brain ischemia and molecular mechanisms in ischemic blood-brain barrier responsible for Alzheimer’s disease and cerebral amyloid angiopathy pathogenesis (Figure 1). First, we discuss ischemic changes, including vascular degeneration that contributes to different stages of the disease process in Alzheimer’s disease (Pluta et al. 2010). We next discuss the role of the ischemic blood-brain barrier, a key β-amyloid peptide transportation system in- and outside brain, whose pathology is observed early in Alzheimer’s disease (Pluta 2007b). Finally, we present characteristic behavioral changes for Alzheimer’s disease following ischemic brain injury. The functional alterations were shown within areas of selective vulnerability to ischemia and they precede neuronal death. After brain ischemia locomotor hyperactivity positively correlated with increased hippocampal neuronal alterations (Pluta et al. 2010). Following brain ischemia impairment in habituation and reduced anxiety were observed. Ischemic brain injury results in reference and working memory deficits. Moreover, ischemic brain injury in experimental animals leads to progression of spatial memory for up to 1 year. Above abnormalities were connected with significant brain atrophy (Figure 2), associated with diffuse neuronal loss in the brain cortex, and in the CA1 sector of the hippocampus (Pluta et al. 2010). Taken together supportive evidence from both experimental and clinical studies indicates that the decline in progressive cognitive activities could not be explained only by direct contribution of primary ischemic brain injury, but rather by a progressive result of the additive effects of the ischemic lesions, Alzheimer’s factors and aging. On the other hand, the abnormal ischemic expression and metabolism of amyloid precursor protein and ischemic injury properly may constitute a vicious cycle, which leads to repeated ischemic type neurodegeneration and finally to full cognitive decline of Alzheimer’s type (Figure 3). Most importantly data from our animal model has shown that senescent systems do retain some capacity for regeneration and functional recovery after ischemic injury. The data presented here support an essential role of brain ischemia and ischemic blood-brain barrier mechanisms in contributing to both, onset and progression of Alzheimer’s disease (Figure 1).
Acknowledgements. This study was supported in part by founds from: Medical Research Centre (T5), Polish Ministry of Science and Higher Education (2007-2010-Cost/253/2006) and European Union (Cost Action B30).
References
1. Pluta R.: Ischemia-reperfusion pathways in Alzheimer’s disease. Nova Science Publishers, New York. 2007a.
2. Pluta.: Role of ischemic blood-brain barrier on amyloid plaques development in Alzheimer’s disease brain. Curr. Neurovasc. Res., 4, 121-129, 2007b.
3. Pluta R, Ułamek M, Jabłoński M.: Alzheimer’s mechanisms in ischemic brain degeneration. Anat. Rec., 292, 1863-1881, 2009.
4. Pluta R, Januszewski S, Jabłoński M, Ułamek M.: Factors in creepy delayed neuronal death in hippocampus following brain ischemia-reperfusion injury with long-term survival. Acta Neurochir., (Suppl.) 106, 37-41, 2010.
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Pluta
R,
Kiryk
A,
Ułamek
M,
Kaczmarek
L and
Jabłoński
M
(2010). AN EXPERIMENTAL MODEL FOR THE ALZHEIMER PHENOTYPE OF
COGNITIVE DEFICITS.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00018
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Received:
10 Mar 2010;
Published Online:
10 Mar 2010.
*
Correspondence:
Ryszard Pluta, Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Ischemic and Neurodegenerative Brain Research, Department of Neurodegenerative Disorders, Granz, Poland, pluta@cmdik.pan.pl