Alzheimer disease as a vascular disorder: Where do mitochondria fit? Sónia C. Correia a, b , Renato X. Santos a, b , Susana Cardoso a, b , Cristina Carvalho a, b , Emanuel Candeias a, b , Ana I. Duarte a , Ana I. Plácido a, c , Maria S. Santos a, b , Paula I. Moreira a, d, ⁎ a Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal b Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal c Faculty of Medicine, University of Coimbra, Coimbra, Portugal d Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal abstract article info Article history: Received 1 April 2012 Received in revised form 12 July 2012 Accepted 13 July 2012 Available online 21 July 2012 Section Editor: Christian Humpel Keywords: Alzheimer disease Cerebrovasculature Mitochondrial dynamics Mitochondrial metabolism Mitochondrial turnover Neurons Although the precise culprit in the etiopathogenesis of Alzheimer disease (AD) is still obscure, defective mitochondria functioning has been proposed to be an upstream event in AD. Mitochondria fulfill a number of essential cellular functions, and it is recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal and vascular homeostasis. Extensive research in postmortem brain tissue from AD subjects, and AD animal and cellular models revealed that mitochondria undergo multiple malfunctions during the course of this disease. The present review summa- rizes the current views on how mitochondria are implicated in both AD-related neuronal and cerebrovascular degeneration. The understanding of the mitochondrial mechanisms underlying AD pathology is critical to design more effective strategies to halt or delay disease progression. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Alzheimer disease (AD) is the most common age-related disorder, which affects more than 35 million people worldwide (Querfurth and LaFerla, 2010). The clinical symptoms of AD are characterized by a pro- gressive cognitive deterioration together with impairments in behavior, language, and visuospatial skills, culminating in the premature death of the individual (Querfurth and LaFerla, 2010). These traits are accompa- nied by neuropathological features observed in postmortem AD brains, including a selective neuronal and synaptic loss in cortical and subcorti- cal regions, deposition of extracellular senile plaques, mainly composed of amyloid-β (Aβ) peptide, presence of intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein, and cerebral amyloid angiopathy (CAA) (Querfurth and LaFerla, 2010). Increasing literature supports a vascular–neuronal axis in AD since shared risk factors for AD, vascular dementia and cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD (Humpel, 2011). In this sense, AD can be considered a vascular disorder. Over the last decades several hypotheses have emerged in an attempt to explain the mechanisms underlying the complexity of AD pathology. Until recently, the most prevailing hypothesis was the “amyloid cascade hypothesis,” which proposes that pathological assemblies of Aβ are the cause of both sporadic and familial forms of AD (sAD and fAD, respectively), whereas other neuropathological alterations are downstream consequences of an abnormal Aβ accu- mulation (Hardy and Selkoe, 2002). However, Aβ has not been proven to be required for the onset and progression of sAD (Hoyer, 2004). Therefore, Swerdlow and Khan proposed the “mitochondrial cascade hypothesis,” which explains many of the biochemical, genetic and path- ological features of sAD (Swerdlow and Khan, 2004). According to this hypothesis: (1) inheritance determines mitochondrial baseline function and robustness; (2) mitochondrial robustness determines how mito- chondria change with age; and (3) when mitochondrial alterations reach a threshold, AD histopathology and symptoms ensue (Swerdlow and Khan, 2004). Meanwhile, a “chicken-and-egg” dilemma still per- sists: is mitochondrial dysfunction the cause of Aβ overproduction or is Aβ overproduction the trigger of mitochondrial dysfunction? The first part of this review is aimed to critically discuss and sum- marize the current knowledge regarding the involvement of mito- chondria in AD-related neuronal degeneration, putting focus on mitochondrial biogenesis, dynamics, and turnover. Considering that the vascular component of AD, which translates very early into cere- bral hypoperfusion, may contribute to neuronal and cognitive deficits (Benarroch, 2007), the second part of this review highlights the role of cerebrovascular abnormalities in the onset of AD pathology and emphasizes the possible pathogenic implications of mitochondria in Experimental Gerontology 47 (2012) 878–886 ⁎ Corresponding author at: Center for Neuroscience and Cell Biology, Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000–354 Coimbra, Portugal. E-mail addresses: venta@ci.uc.pt, pimoreira@fmed.uc.pt (P.I. Moreira). 0531-5565/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2012.07.006 Contents lists available at SciVerse ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero