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F5‐04‐06: Cannabinoids in neuroinflammation and neurogenesis: From normal aging to Alzheimer's disease models
Author(s) -
Marchalant Yannick
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.2348
Subject(s) - neuroinflammation , neurogenesis , inflammation , amyloid (mycology) , disease , amyloid precursor protein , medicine , amyloid beta , neuroscience , genetically modified mouse , neurodegeneration , cannabinoid , alzheimer's disease , transgene , psychology , biology , pathology , receptor , biochemistry , gene
of dementia. This information might lead to more effective therapies that can slow the progression of the degeneration. The degeneration or dysfunction of the temporal lobe and forebrain cholinergic neurons are responsible for aspects of the dementia and are likely due to the selective negative effects of chronic neuroinflammation. I will present results from a series of studies in my laboratory that provide insight into how regional and cellular vulnerability is due to an interaction of three independent factors: the duration of the neuroinflammation, age and gender. Methods: We determined the time course and regional changes associated with both normal aging or the intraventricular or intrathecal infusion of LPS using a series of markers that discriminate proor anti-inflammatory microglia states. The timeand age-dependent effects of LPS-induced brain inflammation and the influence of normal aging upon regional changes in microglial activation will be determined using complementary methods. Young (3 months) and aged (24 months) male F-344 rats will have aCSF or LPS chronically infused into the 4th ventricle for up to eight weeks. Behavioral testing using the Morris water pool task was performed prior to sacrifice for determination of biochemical and histological evidence of the consequences of the chronic neuroinflammation. Results: The loss of forebrain acetylcholine neurons and memory impairment are time-dependent, particularly vulnerable to the action of tumor necrosis factor-alpha and can be reversed in multiple ways. In contrast to males, female rats demonstrate a unique pattern of microglia activation and show no cognitive impairment in the presence of chronic neuroinflammation. The removal of the ovaries impairs performance in females given chronic neuroinflammation. The pattern of activated microglia evolves over a period of six weeks from being uniformly distributed during the first few days to being concentrated within temporal lobe and basal forebrain regions after four weeks of LPS infusion. The microglia of aged rats are less vulnerable to the effects of LPS and less responsive to anti-inflammatory therapy. Conclusions: Chronic neuroinflammation is responsible for the selective vulnerability of specific neural systems and brain regions associated with age-related neurodegenerative changes.