Findels MA 2007

Associate editor: M.M. Mouradian

The role of amyloid

β

peptide 42 in Alzheimer's disease

Mark A. Findeis



Satori Pharmaceuticals Incorporated, 222 Berkeley Street, Suite 1040, Boston, MA 02116, USA

Abstract

During the last 20 years, an expanding body of research has elucidated the central role of amyloid precursor protein (APP) processing andamyloid

β

peptide (A

β

) production in the risk, onset, and progression of the neurodegenerative disorder Alzheimer's disease (AD), the most common form of dementia. Ongoing research is establishing a greater level of detail for our understanding of the normal functions of APP, its proteolysis products, and the mechanisms by which this processing occurs. The importance of this processing machinery in normal cellular function, such as Notch processing, has revealed specific concerns about targeting APP processing for therapeutic purposes. Aspects of AD that are now well studied include direct and indirect genetic and other risk factors for AD, APP processing, and A

β

production. Emerging from thesestudies is the particular importance of the long form of A

β

, A

β

42. Elevated A

β

42 levels, as well as particularly the elevation of the ratio of A

β

42to the shorter major form A

β

40, has been identified as important in early events in the pathogenesis of AD. The specific pathological importanceof A

β

42 has drawn attention to seeking drugs that will selectively lower the levels of this peptide through reduced production or increasedclearance while allowing normal protein processing to remain substantially intact. An increasing variety of compounds that modulate APP processing to reduce A

β

levels are being identified, some with A

β

Keywords:

Alzheimer's; A

β

42; Amyloid;

β

-Peptide; Misfolding; Notch; Secretase

Abbreviations:

A

β

, amyloid

β

peptide; A

β

X

, amyloid

β

peptide of the length specified by

X

, starting at residue 1; AChEI, acetylcholinesterase inhibitor; AD,Alzheimer's disease; AICD, amyloid precursor protein intracellular domain; APP, amyloid precursor protein; ATP, adenosine triphosphate; CHO, Chinese hamster ovary; CNS, central nervous system; COX, cyclooxygenase; CSF, cerebrospinal fluid; CTF, C-terminal fragment; DS, Down's syndrome; ELISA, enzyme-linkedimmunosorbent assay; IDE, insulin-degrading enzyme; IP-MS, immunoprecipiation

–

mass spectrometry; LBD, Lewy body dementia; LOAD, late onset Alzheimer'sdisease; LTP, long-term potentiation; NAC, non-amyloid component; NICD, Notch intracellular domain; NMDA,

N

-methyl-

D

-aspartate; NSAID, non-steroidal anti-inflammatory drug; PD, Parkinson's disease; PS, presenilin; ROCK, Rho kinase; ROS, reactive oxygen species; SDS, sodium dodecyl sulfate; SORL1, neuronalsortilin-related receptor; Tbx21, gene encoding T-helper cell Type 1 specific transcription factor T-bet.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2672. Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2672.1. Amyloid

β

peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2672.2. Genetics of Alzheimer

’

s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2682.3. Other risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2682.4. The normal role of amyloid precursor protein and amyloid

β

peptide . . . . . . . . . . 2682.5. Histopathology of Alzheimer

’

s disease . . . . . . . . . . . . . . . . . . . . . . . . . . 2693. Amyloid

β

peptide 42 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2693.1. A

β

42 levels in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2693.2. The ratio of A

β

42 to A

β

40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

Pharmacology & Therapeutics 116 (2007) 266

–

286www.elsevier.com/locate/pharmthera



Tel.: 617 482 2333; fax: 617 482 3337.

E-mail address:

3.3. Cholesterol, amyloid precursor protein processing, and Alzheimer

’

s disease . . . . . . . 2703.4. Modulators of amyloid precursor protein processing . . . . . . . . . . . . . . . . . . . 2713.4.1. Selectivity for A

β

42 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2713.4.2. Promotion of amyloid precursor protein/A

β

42 clearance . . . . . . . . . . . . 2744. Amyloid

β

peptide misfolding, aggregation, and deposition . . . . . . . . . . . . . . . . . . . 2754.1. Amyloid

β

peptide preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2754.2. Biochemical and cellular studies of amyloid

β

peptide . . . . . . . . . . . . . . . . . . 2764.2.1. Toxicity of A

β

42 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2764.3. Structure of amyloid

β

peptide amyloid fibrils . . . . . . . . . . . . . . . . . . . . . . 2775. The

γ

-secretase complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2776. Amyloid precursor protein processing and other related protein

–

protein interactions . . . . . . 2777. Amyloid precursor protein

–

adaptor protein interactions . . . . . . . . . . . . . . . . . . . . . 2788. Analysis of amyloid

β

peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2789. Current therapy for Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27910. Experimental therapy for Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . 27910.1. Novel therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27910.2. Clinical development of new therapeutics . . . . . . . . . . . . . . . . . . . . . . . . 28011. Drug development of A

β

42-selective lowering agents. . . . . . . . . . . . . . . . . . . . . . 28012. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

1. Introduction

Alzheimer's disease (AD) is the most common neurodegen-erative disease. The estimated number of individuals afflictedwith this disease is now approaching 5 million in the UnitedStates alone (Hebert et al., 2003). In the United States, the totalfinancial cost of this disease exceeds $100 billion dollars(Brookmeyer et al., 1998). The demographics of the aging of thegeneral population lead to projections that the incidence of ADwill continue to escalate over the next several decades. In light of the high incidence of AD expected in such an aging population, the importance of developing a sufficient under-standing of this disease that allows the development of moreeffective diagnosis and treatment continues to increase. Thisreview discusses the processing of amyloid precursor protein(APP), the biochemistry and biology of its proteolytic product,amyloid

β

peptide (A

β

), the role of the long form of A

β

42 inAD and its potential as a target for disease modifying drugdevelopment.

2. Alzheimer's disease

AD is a dementia characterized by progressive loss of memory and one or more other diagnostic criteria. Among themost commonly used criteria are those described in the

Diag-nostic and Statistical Manual of Mental Disorders

(AmericanPsychiatric Association, 2000) and the criteria of the NationalInstitute of Neurological and Communicative Disorders andStroke and the Alzheimer's Disease and Related DisordersAssociation (McKhann et al., 1984). Historically, AD diagnosiswas made after exclusion of all other possible causes of dementia, including metabolic imbalances, such as vitamindeficiencies,orotherneurologicaldisorderswithmoredefinitivediagnostic criteria. Today, clinical diagnosis is still limited to

“

probable

”

or

“

possible

”

AD. Unequivocal diagnosis of definiteAD continues to require postmortem histological analysis of the brain to document the presence of the characteristic senile plaques and tangles that define the disease, at least in later stage

“

classical

”

examples.Earlydescriptionsofthehistopathologyof amyloid deposits led to the correlation of amyloid with thedisease by Alzheimer and the subsequent naming of this diseasefor him. Between these observations, at the turn of the last century and the last quarter of the 20th century, little progresswas made in understanding the etiology of this disease. Perhapsone aspect of this situation is that the single, greatest risk factor for acquiring AD is age. As the general health of the public andthe quality and availability of medical care and medicinesimproved over the last two centuries, the average life span in themore developed parts of the world increased so that theincidence and prevalence of AD increased with the increase inlife span. As AD has become more common, it has become anincreasingly major societal burden, not only to those afflictedwith the disease but also to their families and caregivers. Thus,ADisaveryserious publichealthcareproblem that willbecomeof increasing concern in the future. Consequently, researchershave devoted an increasing amount of effort to improving our understanding of this devastating disease and the ways in whichwe may be able to develop effective therapies.

2.1. Amyloid

β

peptide

One of the most important early discoveries in understandingthe etiology of AD was that the primary component of the AD-associated amyloid deposits in AD brains was an approximately40-residue long peptide, now most commonly known as A

β

(Fig. 1;Glenner & Wong, 1984a,b; Masters et al., 1985; Wong et al., 1985), which was promptly cloned (Kang et al., 1987; see also Swiss-Prot entry P05067,http://www.expasy.org/uniprot/ P05067for additional references). These reports and other earlystudies spurred a rapid growth in research directed towards a

267

M.A. Findeis / Pharmacology & Therapeutics 116 (2007) 266

–

286

better understanding of AD and the identification of potentialapproaches to the development of drugs to treat this disease(Fig. 2). Subsequent research established that A

β

is the product of the proteolytic processing of its precursor,

β

-APP (or simplyAPP), resulting from sequential cleavage by proteases named

β

- and

γ

-secretases (Younkin, 1998; Selkoe, 2001a,b).Importantly, proteolytic processing of APP to create A

β

wasfound to be somewhat heterogeneous, resulting in the production of variable lengths of A

β

, particularly at thecarboxyl terminus of the peptide. The two major forms of A

β

that have been observed to be produced under normalconditions of APP processing are 40 and 42 residues in length(A

β

40 and A

β

42, respectively). In a normal individual, themajority of the A

β

produced is of the shorter variety, A

β

40(Younkin, 1998). About 5

–

15% of the total A

β

pool is A

β

42,and smaller amounts of other A

β

s, both longer and shorter, may be observed. Similar dose responses to inhibitors of A

β

production supported the conclusion that both A

β

40 andA

β

42 are produced by a single

γ

-secretase enzyme (Durkin et al., 1999).

2.2. Genetics of Alzheimer

’

s disease

Three genes are associated with early onset familial AD:APP, presenilin-1 (PS-1), and PS-2 (Hardy, 1997; Tilley et al.,1998). Mutations in these genes, inherited in an autosomaldominant manner, cause AD. Although these mutations account for only a small proportion of total AD cases, they point to acentral theme in AD because they all affect APP processing andA

β

production. Mutations in the APP gene on chromosome 21either increase total A

β

levels or just A

β

42 alone (Jankowskyet al., 2004). Mutations in the PS-1 gene (on chromosome 14)and the much smaller number of known mutations in the PS-2gene (on chromosome 1) all result in an increase in the production of A

β

42 (e.g., seeTomita et al., 1997). Anadditional aspect of the importance of A

β

in AD etiology isthat in Down's syndrome (DS, trisomy 21), an extra copy of chromosome 21 is assumed to result in an increased APPexpression and a corresponding increase in A

β

levels, which are believed to correspond to increased AD-like deposition of amyloid plaques in those individuals with DS. DS brains showsignificant intraneuronal accumulation of A

β

42 (Mori et al.,2002) without increased expression of APP (Argellati et al.,2006). Familial APP mutations, which are associated with earlyonset AD, increase A

β

42 by a factor of 1.5

–

1.9, although A

β

40remains the main A

β

species (Suzuki et al., 1994). In Chinesehamster ovary (CHO) cells that stably express mutant PS genes,A

β

42 production is increased 1.4- to 2.5-fold, and A

β

oligomerization is enhanced (Xia et al., 1997).Additional susceptibility genes have been identified toinfluence the risk of acquiring AD, primarily with regard tosporadic late-onset AD (LOAD). Early studies directed at genesassociated with sporadic LOAD identified different alleles of apolipoprotein E as a risk factor for AD with the A4 alleleassociated with greater risk (Mahley et al., 2006). Another generecently identified as associated with LOAD is that of theneuronalsortilin-relatedreceptorSORL1(Rogaevaetal.,2007).Other genes associated with AD risk include those encodinglipoprotein receptors,

α

1 antichymotrypsin,

α

2 macroglobulin,andbutyrylcholinesterase(Tilleyetal.,1998).Single-nucleotide polymorphisms in the urokinase-type plasminogen activator geneonchromosome10qareassociatedwithelevatedA

β

42andincreased risk of LOAD (Ertekin-Taner et al., 2005).

2.3. Other risk factors

In addition to age, a variety of risk factors are associated withLOAD (http://www.alz.org/alzheimers_disease_causes_risk_ factors.asp). Factors that are associated with increased risk of acquiring AD include a family history of the disease,cardiovascular disease, diabetes, hypertension, heart disease, prior head injury, high alcohol intake, and stroke. Regular exercise, higher education, and proper diet have been reportedto be protective, as has smoking (Lee, 1994), despite its other negative health effects.

2.4. The normal role of amyloid precursor protein and amyloid

β

peptide

The normal roles of APP and its fragments, including A

β

,are less well understood than the extent to which the toxicity of

Fig. 2. Growth in research into the causes and potential treatments of AD. Graphof the number of publications in a specified calendar year as cited in PubMed for the period 1900

–

2006, as of early March 2007. Searches were performed with asingle keyword using

“

Alzheimer

”

( ),

“

dementia

”

(

□

), or

“

senility

”

(

▪

).Fig. 1. Sequence of A

β

and adjacent sequences at proteolytic cleavage sites within APP. Numbering corresponds to the convention for A

β

. Main cleavage sites areindicated for

β

-,

α

-, and

γ

-secretases.268

M.A. Findeis / Pharmacology & Therapeutics 116 (2007) 266

–

286

Category:	Uncategorized.
Rating:
Upload Date:	01/20/2009
Copyright:	Attribution Non-commercial
Tags:	This document has no tags.

Documents

People