Swerdlow RH. Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 28: 1465-1480
Department of Neurology, University of Virginia Health System, McKim Hall, 1 Hospital Drive, P.O. Box 800394, Charlottesville, VA 22908, United States. Neurobiology of aging
(Impact Factor: 5.01).
11/2007; 28(10):1465-80. DOI: 10.1016/j.neurobiolaging.2006.06.021
For 70 years after Alois Alzheimer described a disorder of tangle-and-plaque dementia, Alzheimer's disease was a condition of the relatively young. Definitions of Alzheimer's disease (AD) have, however, changed over the past 30 years and under the revised view AD has truly become an age-related disease. Most now diagnosed with AD are elderly and would not have been diagnosed with AD as originally conceived. Accordingly, younger patients that qualify for a diagnosis of AD under both original and current Alzheimer's disease constructs now represent an exceptionally small percentage of the diagnosed population. The question of whether pathogenesis of the "early" and "late" onset cases is similar enough to qualify as a single disease was previously raised although not conclusively settled. Interestingly, debate on this issue has not kept pace with advancing knowledge about the molecular, biochemical and clinical underpinnings of tangle-and-plaque dementias. Since the question of whether both forms of AD share a common pathogenesis could profoundly impact diagnostic and treatment development efforts, it seems worthwhile to revisit this debate.
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- "In this context, we and a growing number of other investigators have started to think that sAD should be understood from a new perspective, i.e., aging (Chen, 1998; Swerdlow, 2007; Yankner et al., 2008; Castellani et al., 2009; Herrup, 2010; Sperling et al., 2011; Korczyn, 2012). From this ground, we have proposed a new hypothesis for the natural history of sAD (Figure 1). "
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ABSTRACT: Sporadic Alzheimers disease (sAD) has not been explained by any current theories, so new hypotheses are urgently needed. We proposed that energy and Ca2+ signaling deficits are perhaps the earliest modifiable defects in brain aging underlying memory decline and tau deposits (by means of inactivating Ca2+-dependent protease calpain). Consistent with this hypothesis, we now notice that at least eight other known calpain substrates have also been reported to accumulate in aging and AD. Thus, protein accumulation or aggregation is not a pathogenic event, but occurs naturally and selectively to a peculiar family of proteins, and is best explained by calpain inactivation. Why are only calpain substrates accumulated and how can they stay for decades in the brain without being attacked by many other non-specific proteases there? We believe that these long-lasting puzzles can be explained by calpains unique properties, especially its unusual specificity and exclusivity in substrate recognition, which can protect the substrates from other proteases attacks after calpain inactivation. Interestingly, our model, in essence, may also explain tau phosphorylation and the formation of amyloid plaques. Our studies suggest that a-secretase is an energy-/Ca2+-dual dependent protease and is also the primary determinant for A beta levels. Therefore, beta- and gamma-secretases can only play secondary roles and, by biological laws, they are unlikely to be positively identified. This study thus raises serious questions for policymakers and researchers and these questions may help explain why sAD can remain an enigma today.
Available from: Shaharyar Khan
- "Initial versions claimed that plaque Aβ caused AD; current versions claim that Aβ oligomers cause AD . The amyloid cascade hypothesis etiologically lumps late-onset AD (LOAD) with FAD, and de-emphasizes potential connections between LOAD and aging . It presumes that FAD-based disease models model LOAD. "
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ABSTRACT: Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction and Neurodegenerative Diseases.
Available from: Michael Felix Fenech
- "Alzheimer'sdisease(AD)isthemostcommoncauseof dementiaoccurringinmiddleandlatelife.Populationbased surveysestimatethatADaffects7–10%ofindividuals>65yearsof ageandpossibly50–60%ofpeopleover85yearsofage.ADnow affectsabout2%ofthepopulation,orabout4millionpeopleinthe USAandmorethan35millionpeopleworldwide.The prevalenceofADisincreasingproportionallytoincreasedlife expectancyandestimatespredictthattheprevalencewillreach approximatelyover100millionworld-widebymiddleofthis century. Ithasbeenreportedthatmitochondrialabnormalitiescorrelate withdystrophicneurites,thelossofdendriticbranchesandthe pathologicalalterationofthedendriticspinespresentinthebrains ofAlzheimer'sdisease(AD)cases.SwerdlowandKhan  proposedthemitochondrialcascadehypothesistoexplainlateonset ,sporadicAD,statingthatAbdepositionasplaques, neurofibrillarytangleformationandneurodegenerationare consequenteventsofmitochondrialmalfunction.Thishypothesis emphasizesageingasthemainriskfactorforthedevelopmentof thesporadicformofAD.Inparticularitpostulatesthatthe accumulationofAb42,thetoxicformofAbduetoinappropriate processingofamyloidprecursorproteins,isaconsequenceof ageingratherthanthecauseoftheevolutionofthe neuropathologyasiswidelyreportedinthecaseoffamilialAD. Ab42canbetransportedtomitochondriawhereitmayadversely interactwithmitochondrialelectrontransportchainproteins, causeanincreaseinROSproduction,promoteexcessaccumulation ofmitochondrialcalciumions,decreasethenumberoffunctionally activemitochondriaand,ultimately,neurondamage    .In turn,productionofreactiveoxygenspecies(ROS),ATPproduction failure,andpotentialdisruptionofmitochondrialmembranecould causeopeningofmitochondrialpermeabilitytransitionpores, releaseofcytochromec,andinductionofapoptosis. "
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ABSTRACT: Mitochondria are essential for mammalian and human cell function as they generate ATP via aerobic respiration. The proteins required in the electron transport chain are mainly encoded by the circular mitochondrial genome but other essential mitochondrial proteins such as DNA repair genes, are coded in the nuclear genome and require transport into the mitochondria. In this review we summarize current knowledge on the association of point mutations and deletions in the mitochondrial genome that are detrimental to mitochondrial function and are associated with accelerated ageing and neurological disorders including Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis (ALS). Mutations in the nuclear encoded genes that disrupt mitochondrial functions are also discussed. It is evident that a greater understanding of the causes of mutations that adversely affect mitochondrial metabolism is required to develop preventive measures against accelerated ageing and neurological disorders caused by mitochondrial dysfunction.
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