Perhaps one of the most striking features of the conference this year, reflecting the state of research on AD in general, is the continued absence of a clear consensus on what is the most relevant neuropathological change in AD. The first of three symposia on Mechanisms of Neurodegenerative Conditions reflected this ambivalence.  Cochaired by D.M. Michaelson (Tel Aviv, Israel) and S.D. Yan (New York), the session included seven presentations (out of eight originally scheduled) that were largely unrelated to each other except, as the title indicated, that each addressed possible means of causing or preventing neuronal degeneration.

On the importance of understanding how neurons die, at least, there does appear to be some agreement. The loss of basal forebrain cholinergic neurons in AD, for example, has previously been proposed to be due to loss of neurotrophic support, i.e., NGF, but the simplest hypothesis, that there is a decrease in NGF in the AD brain, is not supported by published studies. However, Hock (abstract 287) presented evidence for a decrease in mRNA for the high affinity NGF receptor (trkA) in AD parietal cortex samples (with no change in cerebellar levels).  This decline appears to be quite specific since no changes were found for mRNAs of other neurotrophin receptors or for the neurotrophins themselves. Dr. Hock suggested that the reduction in trkA might contribute to basal forebrain neuron degeneration by reducing the uptake of NGF.  He also provided data implicating microglial cells as a potential source of NGF.  A cell line sharing properties with human microglial cells was found to increase NGF synthesis in vitro in response to IL1-beta and TNF, two cytokines that have previously been implicated in AD.  This effect appears to be mediated, at least in part, by NFkB.

NFkB, in turn, has been implicated in the cellular response to oxidative injury. The role of oxidation in AD pathology was addressed by three speakers, each using a different approach.  C. Behl (Abstract 289) reviewed two lines of evidence implicating oxidative injury in neuronal degeneration.  The first relates to the apparent protective effect of estrogens against AD.  A variety of estrogens, and estrogen derivatives, were tested for antioxidant activity and their ability to protect neurons from glutamate or Aβ cytotoxicity.  Only compounds with a hydroxl group were effective, consistent with the antioxidant effects of other phenolic compounds.  The activity does not seem to be mediated by classical estrogen receptors.  The second line of research involved the role of NF-kB. A mutant PC12 cell line that is resistant to Aβ toxicity shows high levels of NFkB.  Dexamethasone treatment, or expression of the super-repressor of NFkB, reverses this resistance, presumably through down-regulating NFkB.  Thus, NFkB is implicated in conferring resistance to oxidative insults.

F. Van Muiswinkel (Abstract 291) also addressed the role of oxidative injury with specific attention to changes in the expression of NADPH-oxidase in AD.  This enzymatic complex is implicated in the respiratory burst associated with microglial activation.  An antibody raised against one of the subunits of this enzyme (p22-phox) was found to stain microglial cells in AD brain tissue, but rarely in control tissue.  Clusters of microglia associated with plaques exhibit immunoreactivity, but so do microglia throughout the rest of the neuropil and in perivascular locations.  This suggests that production of free radicals is likely to be occurring on the part of microglial cells throughout the tissue, not just in plaque areas.

Still within the theme of oxidative injury, the possible contribution of advanced lipid peroxidation end products to neurodegeneration in AD was addressed by Dr. L. Sayre (Abstract 292).  A number of previous studies have demonstrated markers of oxidative change in AD tissue.  One product of lipid peroxidation, 4-hyroxy-2-nonenal (HNE), has also been shown to exhibit cytotoxic effects.  The approach to studying the possible contribution of HNE-modified proteins to AD pathology involved raising antibodies to the more stable complexes of HNE, e.g., HNE-pyrrole or HNE cross-linked proteins, and screening AD tissue using immunostaining. Neurons that are positive for Alz-50, a suspected marker for neurons that will ultimately exhibit tangles, are stained with the HNE antibodies. This led to the speculation that HNE modification of tau might contribute to alterations that alter tau folding, e.g., apposition of the carboxy and terminal ends of the protein, thereby providing exposure of the Alz-50 epitope.  This, or the association of lipophilic and/or amphiphilic molecules with tau, may subsequently lead to altered tau function, thus providing a potential route by which oxidative injury is coupled to tangle formation.

Other hypotheses of neurodegenerative mechanisms were also presented in this session. R. Itzhaki (Abstract 290.) reviewed her group's work on the role of HSV-1 in AD. HSV-1 transcripts are present in a majority of both AD and control brain tissue samples and an interaction between ApoE genotype and HSV-1 was found such that the presence of viral transcripts and the E4 isoform of ApoE confer a significantly higher risk of AD.  In addition, E4 individuals are much more likely to suffer from "cold sores" with reactivation of HSV-1.  Interestingly, a similar risk was not found for herpes keratitis, perhaps, Itzhaki suggested, due to reactivation of the virus in non-neuronal cells in the cornea rather than in neurons, as occurs in AD and in herpes labialis.

E. Masliah (Abstract 293) outlined a hypothesis implicating aggregation of α-synuclein (also known as NACP)  in neurodegeneration.  Mutations in this protein, which is abundant in synapses, have been implicated in a subset of patients with Parkinson's disease.  Transgenic mice expressing α-synuclein under the control of the PDGF promoter exhibit high levels of the protein in the hippocampus, neocortex, and olfactor bulb.  NACP aggregates were found within cortical and hippocampal neurons with a morphology highly reminiscent of Lewy bodies.  No obvious glial changes were found.  Ultrastructurally, inclusions were found within the nuclei and cytoplasm of neurons, although filamentous morphology was lacking.  Masliah proposed that these aggregates might ultimately be toxic although no data were presented on this point.  He suggested that crossing of these transgenic lines with other transgenic models of AD (currently under way) would provide a useful means of examining the interaction of α-synuclein with other components thought to play a role in neurodegenerative diseases.

Turning from the dark side of the force, so to speak, I. Gozes (Abstract 294) brought the audience up to date on activity-dependent neurotrophic factors (ADNF) and a homologous mouse peptide (ADNP) that exhibit remarkably potent (femtomolar) neuroprotective effects in vitro.  These peptides show homology to hp60, a heat shock protein that is upregulated in neurons in response to VIP.  Gozes provided a model involving two-way interactions between neurons and astrocytes whereby the release of VIP leads to release of ADNF from astrocytes which, in turn, protects neurons by up-regulating hp60.  The peptides protect against Aβ toxicity and also show the ability to compensate for a number of the deficits in apoE-deficient mice, including retarded development, decreased cholinergic activity, and learning and memory deficits.  The mechanism of action of these peptides remains to be established.  If the peptides hold up as the potent trophic agents they appear to be, they provide a novel avenue for developing therapeutic strategies to promote neuronal protection in AD and other neurodegenerative diseases.

Overall, one left the session with the feeling that many questions, mostly non-trivial, remain to be answered before the puzzle of neuronal degeneration is solved.—Keith A. Crutcher


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