Presenilins and Alzheimer’s disease: biological functions and pathogenic mechanisms

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. Dementia is associated with massive accumulation of fibrillary aggregates in various cortical and subcortical regions of the brain. These aggregates appear intracellularly as neurofibrillary tangles, extracellularly as amyloid plaques and perivascular amyloid in cerebral blood vessels. The causative factors in AD etiology implicate both, genetic and environmental factors. The large majority of early-onset familial Alzheimer’s disease (FAD) cases are linked to mutations in the genes coding for presenilin 1 (PS1) and presenilin 2 (PS2). The corresponding proteins are 467 (PS1) and 448 (PS2) amino-acids long, respectively. Both are membrane proteins with multiple transmembrane regions. Presenilins show a high degree of conservation between species and a presenilin homologue with definite conservation of the hydrophobic structure has been identified even in the plant Arabidopsis thaliana. More than 50 missense mutations in PS1 and two missense mutations in PS2 were identified which are causative for FAD. PS mutations lead to the same functional consequence as mutations on amyloid precursor protein (APP), altering the processing of APP towards the release of the more amyloidogenic form 1–42 of Aβ (Aβ42). In this regard, the physical interaction between APP and presenilins in the endoplasmic reticulum has been demonstrated and might play a key role in Aβ42 production. It was hypothesized that PS1 might directly cleave APP. However, extracellular amyloidogenesis and Aβ production might not be the sole factor involved in AD pathology and several lines of evidence support a role of apoptosis in the massive neuronal loss observed. Presenilins were shown to modify the apoptotic response in several cellular systems including primary neuronal cultures. Some evidence is accumulating which points towards the β-catenin signaling pathways to be causally involved in presenilin mediated cell death. Increased degradation of β-catenin has been shown in brain of AD patients with PS1 mutations and reduced β-catenin signaling increased neuronal vulnerability to apoptosis in cell culture models. The study of presenilin physiological functions and the pathological mechanisms underlying their role in pathogenesis clearly advanced our understanding of cellular mechanisms underlying the neuronal cell death and will contribute to the identification of novel drug targets for the treatment of AD.

Introduction

Alzheimer’s disease (AD) is the most common form of progressive dementia, currently affecting 17–25 million people worldwide. In Western countries it represents the fourth leading cause of death after heart diseases, cancer and stroke. The major risk factor for AD is age, the prevalence of AD doubles every five years beyond age 65, reaching over 20% for people in the ninth decade of life and over 40% in the population aged 90 years and above (Katzman, 1976). Life expectancy has increased steadily in developed countries since the turn of the century, AD therefore became rapidly a major health problem. In most industrialized countries, the 85 years and older age group is the fastest growing segment of the population over age 65. The combination of increasing prevalence together with the long survival (two to 20 years) after AD diagnosis will put a heavy social and economic burden on family members and society. The annual direct and indirect economic cost associated with AD in the United States were estimated at US$ 80–100 billion (National Institute on Aging, 1998).

AD is a disease of the brain affecting especially temporal and parietal cortex, hippocampus, and amygdala. Clinically it is characterized by declining cognitive function, loss of memory, and late stage decreasing physical functions. The neuropathology is defined by extensive neuronal cell loss and by the characteristic brain lesions first described by Alzheimer (1907): neurofibrillary tangles and amyloid plaques (Alzheimer, 1907). The term amyloid originally means stark like (Virchow, 1854) but it is today used for fibrillary protein aggregates characterized by a β-sheet structure and birefringence under polarized light upon congo-red staining. Amyloid plaques represent extracellular protein aggregates composed in the majority of amyloid β peptide (Aβ) (Glenner and Wong, 1984, Masters et al., 1985b) deposited in the brain parenchyma and in about 80% of AD cases in the wall of cerebral blood vessels (Masters et al., 1985a). Aβ is a 40 to 43 amino-acid proteolysis product of a larger precursor protein, the amyloid precursor protein (APP) (Kang et al., 1987). Neurofibrillary tangles are intra-neuronal protein aggregates in the form of paired helical filaments, mainly consisting of the microtubule associated protein tau (Goedert et al., 1992). Plaques and tangles follow a selective distribution throughout the association cortex and the limbic system. The distribution and quantity of tangles correlate well with clinical symptoms of the disease than the distribution of amyloid plaques does (Braak and Braak, 1991).

Despite considerable effort, a reliable biomarker for AD has not yet been identified and the diagnosis of AD remains limited to an exclusion of other causes. The definite diagnosis of AD is still based on post mortem histopathological demonstration of amyloid plaques and neurofibrillary tangles. Both, environmental and genetic factors are involved in AD etiology, but the key pathogenic events leading to neuronal degeneration and dementia, are not yet fully understood. However, research on AD got a strong momentum from the identification of two novel genes presenilin 1 and 2 (PS1, PS2) causally implicated in the pathogenesis of AD. In this review we will summarize recent results on PS1 and PS2 and their role in the pathogenesis of AD. The analysis of biological and pathological function of presenilins did reinforce the compelling genetic evidence that mechanisms leading to the generation of Aβ are key players in the pathology of AD and also advanced our understanding of molecular and cellular mechanism, involved in neuronal cell death observed in AD.

Section snippets

Genetics of Alzheimer’s disease

Most cases of AD occur sporadically yet, autosomal dominant transmission could be identified in families with early-onset of AD, before the age of 65 years. These cases are relatively rare; worldwide only 120 families are currently known that carry deterministic mutations (St. George-Hyslop, 1998). The most common cause for autosomal dominant familial AD (FAD) are mutations in the presenilin 1 gene on chromosome 14 (Sherrington et al., 1995). These account for 30–50% of all early-onset cases (

Membrane topology

Hydropathy analysis of PS1 (Fig. 2(A)) and PS2 indicates the presence of a hydrophilic amino-terminus followed by ten hydrophobic regions (HR) of at least 15 amino-acids length, which could potentially span the membrane. Most of these segments are connected by small hydrophilic loops, except one longer stretch of mostly hydrophilic residues between HR 7 and HR 8 called the ‘large loop’. Multiple studies aimed to determine the number of transmembrane domains as well as the orientation of the

Transgenic mouse models

Transgenic animal models (conventional, knock-out, and knock-in) are a powerful tool to study the physiological function of a given protein in vivo. That possibility has special importance in a disease like Alzheimer disease where complex biological networks and functions are disturbed. Several groups (De Strooper et al., 1998, Shen et al., 1997, Wong et al., 1997) realized transgenic mice where the expression of the mouse PS1 homologue is ablated by the disruption of the PS1 gene using

Modification of APP processing

APP is cleaved by at least three different, yet unknown, proteolytic activities. The α-secretase which cleaves within the Aβ region thus preventing its formation (Sisodia et al., 1990), cleavage at the amino-terminus of Aβ by the β-secretase and at the carboxy-terminus by the γ-secretase, releasing Aβ (Haass and Selkoe, 1993). The generation of the Aβ from APP has been shown to be a normal processing event in different cell types (Busciglio et al., 1993, Haass et al., 1992, Shoji et al., 1992)

Conclusion

The identification of missense mutation in presenilins clearly advanced the understanding of cellular mechanisms underlying the pathology of AD. There is no doubt that Aβ and in particular Aβ42, is playing a central role in the disease. Yet, the pathologic effects of presenilins are most likely not restricted to the modification of APP processing but might also directly implicate intracellular pathways linked to cell death. In this respect the recent discoveries that presenilins are able to

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