Evidence for the Involvement of Apoptosis-Inducing Factor–Mediated Caspase-Independent Neuronal Death in Alzheimer Disease

• Published in: The American journal of pathology Vol. 176; no. 5; pp. 2209 - 2218
• Main Authors: Yu, Wenfeng, Mechawar, Naguib, Krantic, Slavica, Quirion, Rémi
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.05.2010; American Society for Investigative Pathology
• Subjects: Adult and adolescent clinical studies; Aged; Aged, 80 and over; Alzheimer Disease - pathology; Apoptosis Inducing Factor - metabolism; Biological and medical sciences; Brain - metabolism; Brain - pathology; Caspases - metabolism; Cell Nucleus - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Humans; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Middle Aged; Models, Biological; Neurology; Neurons - metabolism; Neurons - pathology; Organic mental disorders. Neuropsychology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Protein Structure, Tertiary; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Regular; Subcellular Fractions - metabolism; Nervous system diseases; Enzyme; Alzheimer disease; Cysteine endopeptidases; Caspase; Cerebral disorder; Peptidases; Anatomic pathology; Neuron; Cell death; Central nervous system disease; Hydrolases; Degenerative disease; Apoptosis inducing factor
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.2353/ajpath.2010.090496

Accumulating evidence suggests the involvement of caspase-dependent and -independent mechanisms in neuronal cell death in Alzheimer disease (AD). The apoptosis-inducing factor (AIF) is a mitochondrial oxido-reductase originally characterized as a mediator of caspase-independent programmed cell death (PCD). In this postmortem study, we investigated the distribution of AIF and its possible morphological association with pathological features in the hippocampus, as well as entorhinal and medial gyrus of temporal cortices of late stage AD, dementia with Lewy bodies (DLB), and control subjects. In comparison with controls, a significant increase in neuronal AIF immunoreactivity (AIF-ir) was observed in the hippocampus and the superficial layers of entorhinal and medial gyrus of temporal cortices in AD—but not DLB—samples. AIF-ir in neuronal nuclei was also significantly more widespread in AD compared with control and DLB samples. Furthermore, AIF-ir was found to be colocalized with neurofibrillary tangles (NFTs) in AD brains. Interestingly, a significant positive correlation was seen between nuclear AIF-ir and Braak stage in CA1 of the hippocampus as well as in entorhinal and temporal cortices in AD samples. These data show for the first time: (1) the nuclear localization of AIF in the AD brain and (2) its colocalization with NFTs, suggesting a possible involvement of AIF-mediated caspase-independent PCD, at least in the late stage of this neuropathology.