The molecular mechanism responsible for the neurodegeneration in Alzheimer disease is not known; however, accumulating evidence suggests that 3-amyloid peptide (A.8P) contributes to this degeneration. We now report that synthetic A3Ps trigger the degeneration of cultured neurons through activation of an apoptotic pathway. Neurons treated with AIIPs exhibit morphological and biochemical characteristics of apoptosis, including membrane blebbing, compaction of nuclear chromatin, and internucleosomal DNA fragmenta- This idea is consistent with the fact that cultured cells that express a familial AD-linked mutated form of A,8PP produce severalfold more APP than cells expressing the normal A,8PP

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We used primary cultures of cortical neurons to examine the relationship between ␤-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to ␤-amyloid peptide (␤AP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3␤. DKK1 was induced at late times after ␤AP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in ␤AP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by ␤-amyloid and is critically involved in the process of tau phosphorylation.

Aggregates of beta-amyloid peptide (betaAP), the main constituent of amyloid plaques in Alzheimer's brain, kill neurons by a not yet defined mechanism, leading to apoptotic death. Here, we report that both full-length betaAP((1-40)) or ((1-42)) and its active fragment betaAP((25-35)) act as proliferative signals for differentiated cortical neurons, driving them into the cell cycle. The cycle followed some of the steps observed in proliferating cells, including induction of cyclin D1, phosphorylation of retinoblastoma, and induction of cyclin E and A, but did not progress beyond S phase. Inactivation of cyclin-dependent protein kinase-4 or -2 prevented both the entry into S phase and the development of apoptosis in betaAP((25-35))-treated neurons. We conclude that neurons must cross the G1/S transition before succumbing to betaAP signaling, and therefore multiple steps within this pathway may be targets for neuroprotective agents.-Copani, A., Condorelli, F., Caruso, A., Vancheri, C., Sala, A., Giuffrida Stella, A. M., Canonico, P. L., Nicoletti, F., Sortino, M. A. Mitotic signaling by beta-amyloid causes neuronal death.

For over a decade, evidence has mounted that nerve cell death in the CNS is often intimately linked to a process of cell division. Mitotic markers appear in neurons at risk for death in a variety of neurodegenerative conditions, in mouse and in humans. Beyond correlation, studies have shown that experimentally driving the cell cycle in a mature neuron leads to cell death rather than cell division, and blocking cell-cycle initiation can prevent many types of neuronal cell death. This unlikely linkage of cell cycle and cell death pathways is little appreciated among neuroscientists. As only one example, bromodeoxyuridine (BrdU) labeling is often uncritically accepted as proof of neurogenesis when it may well be attributable to a cell cycle-related cell death. This review is meant to enhance appreciation for the relevance of this phenomenon to development and neurodegenerative diseases, in particular the neurodegeneration found in Alzheimer's disease (AD). A brief overview of the participation of mitotic events in human Alzheimer's disease and its mouse models is presented. Against this background, we consider evidence that links various APP (amyloid precursor protein) binding proteins with the cell cycle in Alzheimer's disease. We also examine the role played by oxidative stress as a trigger for cell cycle-related neuronal death. Finally, we discuss the biochemical details of the lethal neuronal cell cycle events and present evidence that non-canonical pathways of DNA replication are probably involved. BackgroundSince the earliest days of neurobiology, the study of neuronal cell death has been a field full of surprises. For example, the very contention that the death of neurons might be a normal part of the developmental program of the brain was greeted initially with great skepticism, and its formal demonstration by Hamburger (1975) and others came as quite a surprise to most workers in the

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The medium collected from cultured astrocytes transiently exposed to the group-II metabotropic glutamate (mGlu) receptor agonists (2 S ,1Ј R ,2Ј R ,3Ј R )-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) or (S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG) is neuroprotective when transferred to mixed cortical cultures challenged with NMDA (Bruno et al., 1997). The following data indicate that this particular form of neuroprotection is mediated by transforming growth factor-␤ (TGF␤). (1) TGF␤1 and -␤2 were highly neuroprotective against NMDA toxicity, and their action was less than additive with that produced by the medium collected from astrocytes treated with DCG-IV or 4C3HPG (GM/DCG-IV or GM/4C3HPG); (2) antibodies that specifically neutralized the actions of TGF␤1 or -␤2 prevented the neuroprotective activity of DCG-IV or 4C3HPG, as well as the activity of GM/DCG-IV or GM/4C3HPG; and (3) a transient exposure of cultured astrocytes to either DCG-IV or 4C3HPG led to a delayed increase in both intracellular and extracellular levels of TGF␤. We therefore conclude that a transient activation of group-II mGlu receptors (presumably mGlu3 receptors) in astrocytes leads to an increased formation and release of TGF␤, which in turn protects neighbor neurons against excitotoxic death. These results offer a new strategy for increasing the local production of neuroprotective factors in the CNS.

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