Differential regulation of inhibitors of apoptosis proteins in Alzheimer's disease brains.

Neuronal degeneration linked to apoptosis can be inhibited by a family of proteins known as inhibitors of apoptosis proteins (IAPs). We examined three members of the IAP family that are implicated in the regulation of neuronal death. We assessed NAIP, XIAP, and cIAP-2 protein levels in the entorhinal cortex of non-demented, cognitively impaired and Alzheimer's disease cases. Levels of paired helical filament-1 (PHF-1), a marker of neurofibrillary tangles, were assessed to determine their relationship to IAP levels. NAIP was decreased in AD cases compared to mildly impaired and unimpaired cases, and this decrease was associated with increased PHF-1 levels. Low NAIP levels were associated with higher Braak and Braak tangle stage and cognitive dysfunction. XIAP levels were higher in AD cases and cIAP-2 levels did not vary with clinical status. Our data suggest that decreased NAIP may place neurons at risk for the development of tangles and apoptosis.

Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death.

It has recently been suggested that neuronal cell death in response to many brain insults may be mediated by the upregulation of tumor necrosis factor receptor (TNFR) family members and their ligands. In the present study, we investigated whether the expression of the TNFR family death domain receptor, Fas, and its ligand, FasL, is altered in association with neuropathology and activated caspase markers in Alzheimer disease (AD) brain, and Abeta-induced neuronal cell death in vitro. To evaluate this hypothesis, we examined Fas and FasL expression in AD and control brain, and Abeta-treated primary neurons, using immunocytochemistry and Western blots. Neurons in both AD brain and Abeta-treated cultures exhibited FasL upregulation and changes in immunoreactivity for Fas receptor. Further, FasL expression was remarkably elevated in senile plaques and neurofilament-positive dystrophic neurites, and in association with caspase activation and neuritic apoptosis in AD brain. Based on these and previous data regarding protection of primary neuronal cultures from Abeta(1-42)-induced apoptosis by blockade of Fas-associated death domain signaling, we also tested the hypothesis that dynamic regulation of Fas and FasL may contribute to Abeta-mediated neuronal cell death. Accordingly, neuronal cultures derived from mice carrying inactivating mutations in Fas (Faslpr) or FasL (Fasgld) exhibited protection from Abeta(1-42)-induced cell death. These findings suggest that Fas-FasL interactions may contribute to mechanisms of neuronal loss and neuritic degeneration in AD.

The induction of the TNFalpha death domain signaling pathway in Alzheimer's disease brain.

The tumor necrosis factor-alpha death domain pathway contributes to cellular degeneration in a variety of conditions. This study investigates the hypothesis that this death domain pathway is progressively induced in the brain during the progression of Alzheimer's disease (AD). AD cases had increased levels of proapoptotic markers including tumor necrosis factor-alpha (TNFalpha), TNF receptor type 1 (TNF-R1), TNF receptor-associated death domain (TRADD), and caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3 times higher than transitional cases. In striking contrast, potentially neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE) inhibitor protein (FLIP) were decreased in AD as compared with age-matched control cases (P < .01). Overall, there was an elevation in proapoptotic elements, including a 5-fold increase in TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate to increased degenerative potential because the downstream effector caspase-3 and product of the TNF pathway was also increased in parallel with enhanced TNF proapoptotic conditions. Our findings suggest that the TNF death receptor pathway and caspases are activated in the early stages of neuronal degeneration in AD.

Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain.

Granulovacuolar degeneration (GVD) is a diagnostic neuropathological feature of Alzheimer's disease (AD). In some neurons, apoptosis has been hypothesized to be a primary mechanism causing neuronal cell death in AD. In this study we investigated CA1 neurons with GVD in AD and Down's syndrome (DS) brain. We demonstrated that activated caspase-3 and a caspase-cleaved cleavage product of the amyloid precursor protein (cAPP) are co-localized in GVD granules, and that these same cells often show nuclear DNA damage. In contrast, activated caspase-8 is present in the cytoplasm but not within the granules of GVD neurons. A caspase-cleavage product of fodrin that accumulates in many AD and DS neurons is not present in GVD granules. These data support a role for the activation of apoptotic mechanisms in selective compartments exhibiting GVD.