Presenilin-1 C410Y Alzheimer Disease Plaques Contain Synaptic Proteins

Abstract

Presenilin-1 (PS-1) mutations are associated with familial Alzheimer's disease (AD). Although beta-amyloid (Abeta) plaques in brain tissue are characteristic of AD patients, space occupying "cotton-wool" plaques (CWPs) lacking dense Abeta cores have also been described in patients with mutations in exon 9 of the PS-1 gene. The composition of CWPs has not been fully described. To better elucidate the composition of these space-occupying plaques, we used immunohistochemistry with antibodies to the synaptic proteins synapsin-1 and synaptophysin, as well as antibodies to tau, Abeta(-42), Abeta(-40), ubiquitin, neurofilament, and glial fibrillary acidic protein. Confocal laser scanning microscopy (CLSM) was utilized to further characterize these plaques. CWPs showed increased synapsin-1 and synaptophysin immunoreactivity relative to the background gray matter. Synaptic protein-containing CWPs occurred in all affected MTL regions, including the granule cell layer of the dentate gyrus, where synaptic terminals are usually sparse. These data suggest that in C410Y PS-1 AD patients, CWPs may constitute a major component of synaptic terminal-specific proteins, and that the C410Y PS-1 mutation may influence either synaptic structure or synaptic protein expression.

Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

“…The L435F mutation was identified in early-onset FAD with cerebral cotton wool plaque neuropathology (Heilig et al, 2010; Rogaeva et al, 2001). The C410Y substitution was one of the first five FAD mutations reported in PSEN1 (Sherrington et al, 1995), and has been extensively characterized including its association with cerebral cotton wool plaques (Haleem et al, 2007; Klunk et al, 2007; Moonis et al, 2005). The L435F or C410Y missense mutation was introduced into Psen1 exon 12 or 11, respectively, by homologous recombination (Figure 1A), and further verified by Southern analysis and sequencing (Figure S1A–C).…”

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

“…We searched for such a correlation and discovered that the majority of “functional” PS1-FAD mutants have been linked with the CWP/SP phenotype in AD patients. These mutations are PS1-ΔE9 (CWP/SP) [28, 29], P264L (CWP/SP) [30] and C410Y (CWP, Parkinsonism) [31] (Table 1). …”

“…The Aβ42/40 ratios and ER Ca 2+ levels were normalized to the corresponding values for the WT (open triangle). The 3 PS1-FAD mutants with confirmed DCP pathology (M139V, M146L, A246E) [31, 44, 45] were plotted as solid circles, the 8 PS1-FAD mutants with confirmed CWP pathology (L166P, P436Q, P264L, ΔE8, E280G, ΔE9, T291P, C410Y) [13–15] were plotted as open circles, and the 2 PS1-FAD mutants with unknown pathology (G384A, L85P) were plotted as diamonds. For remaining 9 PS1-FAD mutants (G217D, K239E, V261F, E273A, L420R, A426P, A431E, R269G, N405S) Aβ42/40 values were not available and these mutants could not yet be plotted.…”

The Role of Synapsins in Neurological Disorders

“…Mutations in exon 9 of the PS-1 gene manifest space-occupying ''cotton-wool'' plaques (CWPs) lacking dense Ab cores. The increased synapsin I and synaptophysin immunoreactivity evident in CWPs suggests their potential involvement in synaptic structure and protein expression [40].…”

“…In addition to their involvement in the conditions discussed above, synapsins have also been linked to conditions like amyotrophic lateral sclerosis (ALS), autism [90], and hyperalgesia [91]. An immunohistochemical investigation of synaptic proteins has revealed differential expression between the two groups of synaptic proteins in the ALS anterior horn of the spinal cord where synaptic vesicle [36] Protein Interactions Synapsin interactions with SORLA in AD [39] Gene mutations PS-1 mutation in AD [40], Synapsin I and II mutations in epilepsy [50][51][52][53], Synapsin II and III mutations in schizophrenia [63][64][65][66][67][68][69][70] Altered epigenetic mechanisms Increased histone modification and decreased promoter DNA methylation in BD [76,77] Immunogenicity Synapsin-specific T cells in MS pathogenesis [82][83][84][85] Post-translational modifications Impaired phosphorylation in HD [88,89], Impaired sumoylation in epilepsy and autism [90] proteins including synapsin I are significantly decreased [92]. In addition, proteomic analysis of the spinal cord in a mouse model of ALS showed under-expression of synapsin II [93].…”