Simon Kaja
Posters-Accepted Abstracts: J Neurol Neurophysiol
Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 5 mi Americans. As such, AD poses a
significant burden on the affected individual, caregivers and society. Most cases of AD are attributed to the sporadic form,
which is believed to be of multifactorial origin. However, several genetic loci etiological for the rare familial form of the disease
have been identified. One of the loci is the group of presenilin proteins, which form the enzymatic core of the γ-secretase
complex. Most of the almost 200 identified familial AD mutations in presenilins are located in the gene encoding presenilin-1,
while presenilin-2 mutations typically cause later onset familial AD. Recent evidence identified the group of presenilin proteins
as potent modulators of intracellular calcium signaling, through potentiation of the intracellular ryanodine receptor, which likely
underlies this phenomenon. This potentiation occurs via the highly evolutionarily conserved N-terminal region of presenilin,
resulting in differential modulation of the ryanodine receptor by presenilin-1 and presenilin-2. The proposed mechanism is
in accordance with previous studies identifying elevated Ca2+ concentrations in the endoplasmic reticulum during AD, and
the critical role of ryanodine receptors in regulating calcium via calcium-induced calcium release. Furthermore, ryanodine
receptors contribute to the pathologic, elevated intracellular Ca2+ concentrations observed in AD. Intriguingly, similar Ca2+
dyshomeostasis occurs during healthy aging, in the absence of known mutations. Utilizing preclinical models for healthy
aging, we have implicated presenilin proteins in the etiology of age-related changes in synaptic signaling and, ultimately, agerelated
deficits in memory and motor coordination. In this keynote talk, the author will summarize the evidence for the group
of presenilin proteins as a novel class of calcium modulators, and discuss the opportunities for targeting presenilin proteins as
novel drug targets for age-related and neurodegenerative diseases, incl. AD.
