Neurodegenerative Disorder: Alzheimer’s Disease

Presenilin Mediated Disruption of Intracellular Calcium Homeostasis in the Pathogenesis of Familial Alzheimer’s Disease.

Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline resulting in memory and language deficits, personality changes, and gradual loss of independence. AD is the most common form of age related dementia, effecting over 5.2 million Americans age 65 years and older[1, 2]. Most cases of AD are idiopathic in nature, however a rare variant, Familial Alzheimer’s Disease (FAD), is related to autosomal dominant mutations in one of three genes: amyloid precursor protein (APP), Presenilin-1 (PS1) or Presenilin-2 (PS2). Representing less than 5% of all AD, FAD is characterized by an early age of onset (<65), and accelerated progression. FAD cases share many similar pathological features as late onset AD such as extracellular deposition of insoluble amyloid-β-peptide plaques (amyloid plaques), intracellular accumulation of hyper phosphorylated Tau protein (neurofibrillary tangles) and neuronal cell loss[3, 4].
It has been hypothesized that neurological changes associated with AD occur before any clinical symptoms present, therefore by studying biomarkers associated with early-onset AD, targeted therapeutic techniques can be developed to both prevent and treat the more prevalent late onset form.[4].
Mutations in PS1 and PS2 are located on chromosomes 14 and 1, respectively, and account for 20-50% of all early-onset cases of AD [5]. Presenilin proteins are thought to have multiple roles in overall cellular function, but most notably act as sub components of an intramembranous protease complex known as γ-secretase. PS-1/PS-2 induced γ-secretase dysf...

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...on disrupted by familial Alzheimer's disease-linked mutations. Cell, 2006. 126(5): p. 981-93.
9. Green, K.N., et al., SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol, 2008. 181(7): p. 1107-16.
10. Sepulveda-Falla, D., et al., Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J Clin Invest, 2014.
11. Bezprozvanny, I. and M.P. Mattson, Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci, 2008. 31(9): p. 454-63.
12. R. Etcheberrigaraya, N.H., L.Neec, J. Princeb, S. Govonid, M. Racchie, R.E. Tanzif, D.L. Alkonb, Calcium Responses in Fibroblasts from Asymptomatic Members of Alzheimer’s Disease Families. Calcium Responses in Fibroblasts from Asymptomatic Members of Alzheimer's Disease Families, 1998. 5(1): p. 37-45.