Synaptic Compensation as a Probable Cause of Prolonged Mild Cognitive Impairment in Alzheimer’s Disease: Implications from a Transgenic Mouse Model of the Disease
Affiliations: [a] Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, NY, USA
| [b] Research Design and Analysis Service, New York State Institute for Basic Research in DevelopmentalDisabilities, NY, USA
| [c] Graduate Program in Biology (Neuroscience), College of Staten Island (CSI), City University of New York (CUNY) Graduate Center, New York, NY, USA
Correspondence:
[*]
Correspondence to: Khalid Iqbal, PhD, Chair, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Tel.: +1 718 494 5259; Fax: +1 718 494 1080; E-mail: khalid.iqbal.ibr@gmail.com.
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.
