Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: Insights into their potential roles for loss of synapses and memory, accumulation of Abeta, and neurodegeneration in a prodromal stage of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia and is pathologically characterized by senile plaques, neurofibrillary tangles, synaptic disruption and loss, and progressive neuronal deficits. The exact mechanism(s) of AD pathogenesis largely remain unknown. With advances in technology diagnosis of a pre-AD stage referred to as amnestic mild cognitive impairment (MCI) has become possible. Amnestic MCI is characterized clinically by memory deficit, but normal activities of daily living and no dementia. In the present study, compared to controls, we observed in hippocampus from subjects with MCI a significantly decreased level of PSD95, a key synaptic protein, and also decreased levels of two proteins associated with PSD95, the N-methyl-D-aspartate receptor, subunit 2A (NR2A) and the low-density lipoprotein receptor-1 (LRP1). PSD95 and NR2A are involved in long-term potentiation, a key component of memory formation, and LRP1 is involved in efflux of amyloid beta-peptide (1-42). Abeta (1-42) conceivably is critical to the pathogenesis of MCI and AD, including the oxidative stress under which brain in both conditions exist. The data obtained from the current study suggest a possible involvement of these proteins in synaptic alterations, apoptosis and consequent decrements in learning and memory associated with the progression of MCI to AD.

Figure 1

‘A’ is a representative Western blot of hippocampal PSD95 protein levels in MCI and age-matched controls. ‘B’ is the bar graph of the PSD95 Western blot results. An arrow indicate the position of PSD 95 on the blot. Control and MCI hippocampal samples were loaded in adjacent lanes. Lanes 1, 3, 5, 7, 9, 11 represent control samples, and lanes 2, 4, 6, 8, 10, 12 represent MCI samples. See text for methods and further details. Data are shown as Mean ±S.D. n=6 , * p<0.05. “C” shows actin levels in Control and MCI samples, and analysis shows no significant difference in actin in MCI hippocampus compared to control hippocampus. See text.

Figure 2

‘A’ is a representative Western blot of hippocampal NR2A protein levels in MCI and age-matched controls. ‘B’ is the bar graph of the NR2A Western blot results. Control and MCI hippocampal samples were loaded in adjacent lanes. Lanes 1, 3, 5, 7, 9, 11 represent control samples, and lanes 2, 4, 6, 8, 10, 12 represent MCI samples. See text for details. Data are shown as Mean ±S.D. n=6 , * p<0.05.

Figure 3

‘A’ is a representative Western blot of hippocampal LRP1 protein levels in MCI and age-matched controls. ‘B’ represents the histogram of the LRP1 Western blot results. Control and MCI hippocampal samples were loaded in adjacent lanes. Lanes 1, 3, 5, 7, 9, 11 represent control samples, and lanes 2, 4, 6, 8, 10, 12 represents MCI samples. See text for details. Data are shown as Mean ±S.D. n=6 , * p<0.05.

Figure 4

‘A’ represents Western blot of hippocampal BCl₂ protein levels in MCI and age-matched controls. ‘B’ represents histogram of BCl₂ blot. Lanes 1-6 represent control hippocampus, and lanes 7-12 represent MCI hippocampus. See text for details. Data are shown as Mean ±S.D. n=6 , * p<0.05.

Figure 5

‘A’ represents Western blot of hippocampal caspase-3 protein levels in MCI and age-matched controls. ‘B’ represents the bar graph of the caspase-3 blot. Lanes 1-6 represent control hippocampus, and lanes 7-12 represent MCI hippocampus. See text for details. Data are shown as Mean ±S.D. n=6 , * p<0.05.