One of the most intriguing features of brain aging is the tremendous variability in the loss of cognitive function and plasticity. Certain individuals function alertly up to 90 years of age whereas others show decline of intellectual ability as their mid-50's and in the extreme form, develop clinical dementia such as Alzheimer's disease. What are the factors that might account for the loss of plasticity and cognitive functions in the aging brain and, what role(s) do they play in the impressive individual variation observed during aging in human and rodent: We are examining molecular mechanisms involved in the CNS reinnervation process that might regulate the abnormal compensatory plasticity reported in brain aging and in Alzheimer's disease. We recently showed that the brain has evolved a powerful mechanism allowing lipid recycling from degenerating neurons to reinnervating ones. This process relies on the synthesis of apolipoprotein E by astrocytes (for lipid transport) and, the up-regulation of its receptor (LDL receptor) by neurons. Preliminary data indicates that this recycling pathway is compromised in patients with Alzheimer's disease and, in lesioned rat exposed to glucocorticoid levels similar to those measured in aged rats. Studies proposed here will examined a) the role played by the LDL receptor during normal reinnervation process in young rats and, b) how it regulates cholesterol synthesis and storage in brain cells. We will also attempt to relate changes in hypothalamic-pituitary-adrenal (HPA) function (glucocorticoid status) to individual differences in hippocampal synaptic plasticity in later life using animal models of both """"""""successful aging"""""""" (low corticosterone level and absence of cognitive decline) and """"""""unsuccessful aging"""""""" (high cort level and presence of cognitive decline). We anticipate to demonstrate a relationship between the loss of cognitive function in aged rats and a glucocorticoids-mediated, cholesterol-recycling-dependent reduction of hippocampal synaptic plasticity. We hope to show that changes in HPA function can be used to predict individual differences in cholesterol recycling and hippocampal plasticity in aged rats. Finally, we will examine whether the loss of apolipoprotein E expression observed in the hippocampus of AD relates to the reported absence of synaptic plasticity in these patients. We will also examine the possibility that cholesterol synthesis and re-uptake could be up-regulated by local hippocampal neurons to compensate for the loss of apolipoprotein E expression. These experiments will allow us to go beyond the variable of chronological age, and examine some of the factors possibly responsible for a decreased synaptic plasticity associated with aging and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010003-02
Application #
2051258
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-09-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Mcgill University
Department
Type
DUNS #
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 0-G4
Ndung'u, M; Hartig, W; Wegner, F et al. (2012) Cerebral amyloid *(42) deposits and microvascular pathology in ageing baboons. Neuropathol Appl Neurobiol 38:487-99
Poirier, J; Beffert, U; Dea, D et al. (1995) Increased levels of statin, a marker of cell cycle arrest, in response to hippocampal neuronal injury. Brain Res Mol Brain Res 34:57-64
Bertrand, P; Poirier, J; Oda, T et al. (1995) Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Brain Res Mol Brain Res 33:174-8
Nalbantoglu, J; Gilfix, B M; Bertrand, P et al. (1994) Predictive value of apolipoprotein E genotyping in Alzheimer's disease: results of an autopsy series and an analysis of several combined studies. Ann Neurol 36:889-95
O'Donnell, D; Baccichet, A; Seckl, J R et al. (1993) Entorhinal cortex lesions transiently alter glucocorticoid but not mineralocorticoid receptor gene expression in the rat hippocampus. J Neurochem 61:356-9
Poirier, J; Baccichet, A; Dea, D et al. (1993) Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience 55:81-90
Poirier, J; Davignon, J; Bouthillier, D et al. (1993) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342:697-9