35

Arson

Tracking the Culprit in Alzheimer’s Disease

MARK A. SMITH,a JAMES A. JOSEPH,b AND GEORGE PERRYa,c

aInstitute of Pathology, Case Western Reserve University,Cleveland, Ohio 44106, USAbJean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street,Boston, Massachusetts 02111-1525, USA

ABSTRACT: By focusing on the lesions in Alzheimer’s disease, and regard-ing them as either critical or irrelevant, researchers may have missed muchregarding the origin and pathogenesis of this disease. In this article we con-sider that the lesions are so obvious not only because they are pathogno-monic for Alzheimer’s disease, but also because they represent a majordeparture from normal physiology. We suggest that these myriad patho-logical changes are homeostatic compensatory mechanisms to aging.

KEYWORDS: Alzheimer’s disease; Amyloid; Antioxidant; Homeostasis

A terrible tragedy is occurring: A house is burning, but luckily the family hasexited the home. We can easily identify the firemen, but distinguishing thefamily from the bystanders as well as determining whether one of them is di-rectly involved in setting the fire requires an investigation. We start our inqui-ry noting the courage of the firemen, the anguish of the family, and theimpediment posed by the bystanders and we consider who could have startedthe fire. Even at this preliminary stage, our investigation is biased by socialcontext, which provides the baseline circumstances. Without this context andthe ability to interview each person at the scene, would it not be reasonableto assail the firemen for the destruction? In fact, firemen would be prime ar-son suspects since they are the earliest at the scene when there are no familymembers or bystanders and, moreover, the firemen often appear destructiveas they smash doors with axes and flood the home with water. Consider, too,

cAddress for correspondence: George Perry, Ph.D., Institute of Pathology, Case WesternReserve University, 2085 Adelbert Road, Cleveland, Ohio 44106. Voice: 216-368-2488; fax:216-368-8964.

gxp7@po.cwru.edu

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the following examples from the field of medicine: Until recently, ulcers wereconsidered the result of an acid secretory imbalance, not a bacterial infection.Artherosclerosis was ascribed simply to cholesterol accumulation rather thanto a major imbalance in normal physiology that may also be caused by infec-tion. In the following pages, we suggest that our understanding of Alzhe-imer’s disease (AD) has similarly suffered due to a focus on either amyloid-β (Aβ) being the cause (arsonist) or an epiphenomenon (bystander), ratherthan an important protective response (fireman). Significantly, appreciationof the latter considers that the restoration of balance, even at the price of fo-cal, proscribed destruction, is a constant theme in biology.

Identification of homeostatic changes has most often been identified inyoung individuals where they restore optimal function. In aging, compensa-tion instead results in suboptimal states that preserve some degree of func-tion. At the neuromuscular junction, while functional innervation ispreserved throughout life, the synapse is enlarged and elaborated with aging.1

Similarly, while synapse number is reduced in AD, the area of each synapsealso increases.2 Could not Aβ and other aspects of AD pathology be compen-satory changes? This might explain why such changes are invariably seen innormal aging, where they have “successfully” preserved normal function,and in AD, where, although the compensations were induced, the primarypathogenic force proved too strong.

While the focus of AD research has been on Aβ as a toxic agent,3 otherstudies have found neurotrophic activity.4 In our own studies of Aβ, we founda gliotic response in a culture model5,6 and, in vivo, a reduction of oxidativedamage.7,8 Are we seeing the fireman with a hook and hose wreaking damageas he fights the inferno, without noting the protection of adjacent houses? Weargue that viewing Aβ as either good or bad is simplistic because neither dowe know the social context (rules), nor have we completed the inquiry as tothe character (properties) of those at the scene. Without knowledge of therules and properties, we can only identify the firemen due to their constantpresence and defining uniform; we may more easily appreciate destructionwithout considering the balance of benefit. Aβ and its precursor, amyloid-βprotein precursor (AβPP) are, by diagnostic definition, always at the patho-logical site in AD. They appear on the scene early in the disease, but the quan-tity of Aβ is not well correlated with cognitive decline. So, while cases of ADhave abundant Aβ deposits, normal aged individuals can also have extensiveAβ deposits, in some cases rivaling those found in AD. Since the prevalenceof normal individuals with Aβ deposits increases with age, as does AD, thisobservation supports the idea of AD as a long festering degenerative process,but is it? If we accept this, we are also accepting that the brain produces a tox-ic response before the disease, not due to defect (genetic mutation), but ratherby design. Since this is a feature unprecedented in biology, we are forced toconclude that, beginning in middle age, more than half the population is pro-

37SMITH & PERRY: THE CULPRIT IN ALZHEIMER’S DISEASE

grammed to self-destruct and that the destruction of man’s intellect is fromwithin.

Biologically, tissue responds to insult (fire) by compensatory changes(firemen). A parallel may be drawn to inflammation, where cellular destruc-tion accompanies the response to infection, but without the response, the vi-ability of the organism is jeopardized and healing will not result. Studiessuggest that Aβ may act as an antioxidant. Significantly, antioxidants canhave context-dependent prooxidant3 as well as antioxidant activity as elec-tron sources.9 One of the pleotrophic aspects of AD is a change in redox state,which provides greater reducing equivalents (e.g., induction of the pentosephosphate pathway).10,11 This means that in AD, Aβ production occurs in thecontext of increased intracellular reducing equivalents, circumstances notseen in cell cultures or in transgenic mice exposed to atmospheric O2 andtherefore not replicating the context of Aβ presentation to neurons as foundin the brains of patients suffering from AD. The fireman is only effective inrestoring balance in the context of a burning house, not any house in theneighborhood; Aβ may also wreak havoc under similar benign settings. Bythe same logic, we would argue that the other genetic factors identified in ADare essential to age-related compensation and that their failure not only leadsto AD, but also necessitates greater compensations (i.e., increased Aβ). Theincreased levels of Aβ seen in the context of presenilin mutations do not ar-gue for Aβ supremacy, but rather that Aβ is an important responder (fireman)to brain imbalance caused by the genetic abnormality.

At the opposite end of the spectrum, the poor correlation of cognitive de-cline and neuronal loss with the extent of Aβ deposition does not require clas-sification of Aβ as a bystander. That mutations in AβPP and presenilins leadto increased Aβ production suggests that Aβ plays a key and essential role inage-related compensation. Our argument that compensations are critical tosuccessful aging is based (1) on the need for remodeling to maintain normalfunction with development and aging12 and (2) on the notion that failure ofthese compensations not only allows development of AD as a default, but alsopresents itself as a robust display of multiple compensations. These compen-sations can easily be identified by how they depart from normal (the fire-man’s uniform) and they can also be reported as the origin of disease, muchas a fireman could be considered a house wrecker if the context for his ap-pearance is unknown.

Rather than viewing Aβ as the origin (arsonist) or bystander, we argue thatother more complex relationships may be more meaningful that classify thesemolecules as neither irrelevant nor all-encompassing. Significantly, viewingthe lesions as compensatory responses places them in the biological realmwhere self-immolation is evolutionarily excluded. Further, our theory sug-gests that modification of Aβ levels will have therapeutic benefit only if itpromotes a protective function and reduces other consequences, perhaps

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analogous to antiinflammatory agents that, while suppressing cellular reac-tion, still allow repair. Most significantly, by employing an investigativemode of reportage, we can move beyond the firemen to identify the arsonist.

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