Loss of Proteins Regulating Synaptic Plasticity in Normal Aging of the Human Brain and in Alzheimer Disease

Abstract

Recent studies suggest that the cognitive impairment associated with normal aging is due to neuronal dysfunction rather than to loss of neurons or synapses. To characterize this dysfunction, molecular indices of neuronal function were quantified in autopsy samples of cerebral cortex. During normal aging, the most dramatic decline was found in levels of synaptic proteins involved in structural plasticity (remodeling) of axons and dendrites. Alzheimer disease, the most common cause of dementia in the elderly, was associated with an additional 81% decrease in levels of drebrin, a protein regulating postsynaptic plasticity. Disturbed mechanisms of plasticity may contribute to cognitive dysfunction during aging and in Alzheimer disease.

Regional protein levels of cytosolic phospholipase A2 and cyclooxygenase-2 in Rhesus monkey brain as a function of age

“…However, a significant decrease in COX-2 mRNA levels in the cortex has been reported in the aged rat [44]. Examination of changes localized to neurons showed an increase of COX-2 protein in aged rats [24,31]. Based upon the induction of COX-2 by inflammatory signals, studies examining transgenic mice developed as models of neurodegenerative disease have reported age related increases in COX-2 protein in transgenic "beta-amyloid precursor protein" Swedish mutation mice leading to the elevated production of pro-inflammatory eicosanoids [43].…”

“…Neuroinflammation and the upregulation of both cPLA 2 and COX-2 has been implicated in age-related neurodegenerative diseases, including Alzheimer's disease [54] yet the experimental data has been less than conclusive of what role these enzymes may play in the process of brain aging. Some studies indicate no differences in COX-2 mRNA and protein levels in the rat brain in relation to age [2,24]. However, a significant decrease in COX-2 mRNA levels in the cortex has been reported in the aged rat [44].…”

“…COX-2 expression is elevated in the newborn rodent brain cortex and periventricular white matter and accounts for a greater percentage of total COX-activity as compared to the adult [32]. Evidence indicates that levels of drebrin, an actin-binding protein localized mainly in dendritic spines, is significantly decreased during healthy aging [24]. In the current study, we compared the protein expression of cPLA 2 and COX-2 in specific brain regions associated with cognitive function and motor coordination (frontal pole, hippocampus, and cerebellum) in normal healthy Rhesus monkeys at three distinct ages: young (2-5 years), middle aged adult (8-11 years) and old (23 years).…”

The role of the drebrin/EB3/Cdk5 pathway in dendritic spine plasticity, implications for Alzheimer’s disease

“…This occurs in mild cognitive impairment (Counts et al, 2012), Alzheimer's disease (Harigaya et al, 1996;Hatanpaa et al, 1999;Shim and Lubec, 2002;Calon et al, 2004;Zhao et al, 2006) and Down's syndrome, where individuals inevitably develop Alzheimer's (Weitzdoerfer et al, 2001;Shim and Lubec, 2002). Whether or not drebrin loss from dendritic spines is causal to cognitive decline in Alzheimer's disease and related cognitive disorders is not fully resolved.…”

“…Although proteolysis at synapses increases in Alzheimer's disease, drebrin breakdown products have not been seen. Proteolytic fragments might have been missed because only one antibody had been used previously to detect drebrin by immunoblotting in Alzheimer's disease brain tissue and transgenic mouse models of Alzheimer's disease and the epitope that it recognises, which is in the C-terminal BB, might be lost from proteolytic fragments (Hatanpaa et al, 1999;Calon et al, 2004;Zhao et al, 2006;Counts et al 2012). It is unclear whether the loss of drebrin through proteolysis causes a loss of drebrin function or a dominant negative effect through one of the proteolytic fragments.…”