Synaptic Compensation as a Probable Cause of Prolonged Mild Cognitive Impairment in Alzheimer’s Disease: Implications from a Transgenic Mouse Model of the Disease

Abstract

Alzheimer's disease (AD) is a slow, progressive neurodegenerative disease in which cognitive decline takes place over a period of several years with a very variable period of mild cognitive impairment (MCI) and, in some cases, relatively long period before progression to dementia. The cognitive deficit during MCI is probably due to neuronal loss, an intermediate level of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) and synaptosis, which is interrupted with a transient compensatory increase. We found impairment in reference memory accompanied by a decrease in the expression of synaptophysin, β-III tubulin, and MAP2 and a trend for GluR1, at 12 weeks of age in 3xTg-AD mice (hAPPSwe, P301L tau, PS1 [M146V] knock-in), a widely used transgenic model of AD. Past 12 weeks, the cross-sectional analysis of different age groups showed a compensatory increase in synaptic markers relative to that in wild type animals in a topographic and time-dependent manner. When studied across time we found that in 3xTg-AD mice, the compensatory phenomenon occurred in parallel in different regions of the brain. However, this attempt of the brain to repair itself was able to only partially rescue cognitive impairment. These findings for the first time raise the intriguing possibility that AD causing mutated transgenes may initially cause an increase in synaptic and dendritic markers as a compensatory mechanism for synaptic deficit, and this phenomenon, though transient, could be the biological basis of the period of MCI seen in AD.

Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels in A Transgenic Murine Model of Alzheimer’s Disease

“…Although these findings could have been expected in light of the lack of massive neuronal loss in the cortex and the hippocampus of 3×Tg-AD mice [23], one prior study reported significant reduced synaptophysin levels in the cerebral cortex of this animal model of AD) [51]. Furthermore, a decrease in the expression of synaptophysin was observed in 3 months-old 3×Tg-AD mice associated with a trend to a compensatory increase relative to that in wild type animals in a topographic and time-dependent manner [52]. The treatment with um-PEA did not affect the marker levels in both genotypes, thus suggesting that under the present experimental conditions oral um-PEA treatment failed to exert neuroprotective effects.…”

Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound

“…At early stages of the disease the brain attempts to repair itself by promoting dentate gyrus neurogenesis and synaptogenesis but, probably because of insufficient appropriate neurotrophic support, this attempt does not succeed beyond a limited time and the degree of dementia keeps advancing [1–7]. Employing 3 × Tg-AD mice as a model of this phenomenon [15], in the present study we found that by providing neurotrophic support with P021 we can rescue synaptic deficit and reverse cognitive impairment. The use of transgenic mouse models has helped understand the molecular mechanisms of AD and has facilitated preclinical studies that could lead to development of potential AD drugs.…”

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

“…Higher levels of SYP correlated with yet normal cognition in older people displaying extensive A brain pathology, compared to cognitively impaired AD patients . In addition, in 3xTg‐AD animal brains, SYP region‐ and time‐selective upregulation appeared even after an initial loss of synaptic components . This compensatory rise was related to partial recovery of cognitive functions, followed by SYP loss as symptoms worsened.…”

“…29 In addition, in 3xTg-AD animal brains, SYP region-and time-selective upregulation appeared even after an initial loss of synaptic components. 37 This compensatory rise was related to partial recovery of cognitive functions, followed by SYP loss as symptoms worsened. In our own recent studies, in a model of slow-developing neuronal damage, obtained by exposing rat organotypic hippocampal slices to sub-lethal concentrations of oAβ42, we showed an initial compensatory increase in SYP levels and vesicle recycling.…”