Synaptic proteins, neuropathology and cognitive status in the oldest-old

Abstract

An increasing number of individuals in our population are surviving to over 90 years and a subset is at risk for developing dementia. However, senile plaque and neurofibrillary tangle pathology do not consistently differentiate individuals with and without dementia. Synaptic protein loss is a feature of aging and dementia and may dissociate 90+ individuals with and without dementia. Synaptophysin (SYN), postsynaptic density 95 (PSD-95) and growth-associated protein 43 (GAP-43) were studied in the frontal cortex of an autopsy series of 32 prospectively followed individuals (92-105 years) with a range of cognitive function. SYN protein levels were decreased in individuals with dementia and increased in those with clinical signs of cognitive impairment insufficient for a diagnosis of dementia. SYN but neither PSD-95 nor GAP-43 protein levels were significantly correlated with mini-mental status examination (MMSE) scores. Frontal cortex SYN protein levels may protect neuronal function in oldest-old individuals and reflect compensatory responses that may be involved with maintaining cognition.

Figure 1.

Quantification of frontal cortex synapse proteins in the oldest-old. All protein levels for individual synapse markers were established based on loading increasing concentrations of pooled homogenates of frontal cortex tissue to establish optimal amounts for quantifying synaptophysin (SYN)

(A) PSD-95 (B) and for GAP-43 (C). Lines indicate either linear or logistic regression. Representative western blots of PSD-95, GAP-43 and SYN are shown for a subset of oldest-old cases used in the current study along with a protein loading control (GAPDH) (D).

Figure 2.

Protein levels as a function of clinical diagnosis in the oldest-old. SYN protein levels were highest in individuals that were cognitively impaired but not demented (CIND) relative to cases with dementia (A). There was no difference in PSD-95 levels in the three clinical groups (B) and there was a trend towards higher GAP-43 in CIND cases (C) This trend was primarily due to one subject with very high GAP-43 protein levels. SYN protein levels in the frontal cortex were also significantly correlated with overall cognitive function measured by the MMSE (r=0.73)(D). However, there was no association between MMSE and PSD-95 (r=0.08) (E) or GAP-43 (r=0.31)(F) protein levels. (F). Lines at the top of graphs in A, B, and C, indicate Bonferroni corrected post hoc comparisons. Horizontal lines in A,B,C represent group means. Individual data points are shown as open circles. Lines in D, E, and F represent linear regression analyses.

Figure 3.

Comparison of synaptic protein levels between nondemented cases with and without tangle pathology to demented cases with and without tangle pathology. (A) SYN levels were highest overall in nondemented individuals with B&B stage > III. (B) PSD-95, however, was lowest overall only in cases with dementia and a B&B stage > III. (C) In contrast, GAP-43 was lowest overall in demented subjects with a B&B Stage < III. Lines at the top of the graphs indicate significant group differences using Bonferroni post hoc comparisons. Individual data points are represented as open circles and means of each group are shown as horizontal lines.