Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease

Abstract

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer’s disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial AD, the etiology of sporadic AD is not fully understood. Our current study shows that changes in conformation of endogenous wild type PS1, similar to those found with mutant PS1, occur in sporadic AD brain and during normal aging. Using a mouse model of Alzheimer’s disease (Tg2576) that overexpresses the Swedish mutation of amyloid precursor protein but has normal levels of endogenous wild-type presenilin, we report that the percentage of PS1 in a pathogenic conformation increases with age. Importantly, we found that this PS1 conformational shift is associated with amyloid pathology and precedes amyloid-β deposition in the brain. Furthermore, we found that oxidative stress, a common stress characteristic of aging and AD, causes pathogenic PS1 conformational change in neurons in vitro, which is accompanied by increased A 42/40 ratio. The results of this study provide important information about the timeline of pathogenic changes in PS1 conformation during aging, and suggest that structural changes in PS1/-secretase may represent a molecular mechanism by which oxidative stress triggers amyloid-β accumulation in aging and in sporadic AD brain.

Three dimensions of the amyloid hypothesis: time, space and 'wingmen'

“…Mice harboring fAD mutations develop neuroinflammation, oxidative stress, mitochondrial dysfunction, and other pathologic alterations which thus appear to be downstream changes which indicate Aβ-induced neuronal or glial injury, though many of these markers appear before significant plaque deposition 102–104 . However, preclinical data suggests that neuronal stressors such as oxidative and nitrative stress 105, 106 , mitochondrial dysfunction 107 , and inflammation 108 , can also directly influence APP metabolism and Aβ accumulation, suggesting the existence of a possible feed-forward mechanism by which Aβ-induced injury can facilitate Aβ production, or by which other stressors, such as ischemia or trauma, might exacerbate Aβ production and toxicity.…”

Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation

“…Hence, we refer to this state as "closed," pathogenic PS1 conformation. Importantly, pathogenic PS1 conformation, elevated production of the longer, fibrillogenic Aβ species and consequent increase in the Aβ42/40 ratio, leading to gradual amyloid deposition, occur during aging, and in sporadic AD brains (14)(15)(16). Of note, the occurence of PS1 conformational change correlates with the proximity to Aβ plaques (15).…”

“…Importantly, pathogenic PS1 conformation, elevated production of the longer, fibrillogenic Aβ species and consequent increase in the Aβ42/40 ratio, leading to gradual amyloid deposition, occur during aging, and in sporadic AD brains (14)(15)(16). Of note, the occurence of PS1 conformational change correlates with the proximity to Aβ plaques (15). On the other hand, compounds that allosterically modulate PS1 by shifting it toward the "open" conformation consequently shift the spectra of Aβ species toward the shorter peptides (11,17,18).…”

“…PS1 exists in the "closed" pathogenic state in neurons proximal to the amyloid deposits (15). To determine whether an increase in the Aβ42 and/or the Aβ42/40 ratio can in turn modulate PS1 subdomain arrangement, we incubated primary neurons with Aβ mixtures containing Aβ42 to Aβ40 in the following ratios: 1:9; 3:7; 4:6; 10:0.…”

The development and treatment of Alzheimer’s disease: Some genetic aspects

“…Патологическими в отношении развития БА являются е4/2, е4/3 и e4/4. Лишь 5% населения имеют ге-нотип АРОЕ е4/4 и 20% (суммарно) -генотипы АРОЕ е4/3 и АРОЕ е4/2 [30].…”