David J. Bonda

Role of metal dyshomeostasis in Alzheimer's disease

Despite serving a crucial purpose in neurobiological function, transition metals play a sinister part in the aging brain, where the abnormal accumulation and distribution of reactive iron, copper, and zinc elicit oxidative stress and macromolecular damage that impedes cellular function. Alzheimers disease (AD), an age-related neurodegenerative condition, presents marked accumulations of oxidative stress-induced damage, and increasing evidence points to aberrant transition metal homeostasis as a critical factor in its pathogenesis. Amyloid-β oligomerization and fibrillation, considered by many to be the precipitating factor underlying AD onset and development, is also induced by abnormal transition metal activity. We here elaborate on the roles of iron, copper, and zinc in AD and describe the therapeutic implications they present.

The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations

BACKGROUND Advances in gerontology have yielded crucial insights into the molecular and biochemical aspects of the ageing process. The sirtuin pathway, which is most notable for its association with the anti-ageing effects of calorie restriction, has received particular attention, and pharmacological or transgenic upregulation of the sirtuin pathway has shown promising results in laboratory models of ageing. Alzheimers disease is a neurodegenerative disease that is imposing an increasing burden on society, and is the leading cause of senile dementia worldwide. The lack of therapies for Alzheimers disease provides a strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a mechanism of action of the sirtuin pathway that might have therapeutic potential for Alzheimers disease. RECENT DEVELOPMENTS SIRT1, one of the seven mammalian proteins of the sirtuin family of NAD(+)-dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid-β protein precursor (APP) in cell culture studies in vitro and in transgenic mouse models of Alzheimers disease. Mechanistically, SIRT1 increases α-secretase production and activity through activation of the α-secretase gene ADAM10. Because α-secretase is the enzyme responsible for the non-amyloidogenic cleavage of APP, upregulation of α-secretase shifts APP processing to reduce the pathological accumulation of the presumptive toxic Aβ species that results from β-secretase and γ-secretase activity. Interestingly, the spatial patterns of Aβ deposition in the brain might correlate with increased aerobic glycolysis in those regions. Because aerobic glycolysis depletes cellular levels of NAD(+) (through a decreased NAD(+)/NADH ratio), it is possible that a corresponding downregulation of the NAD(+)-dependent sirtuin pathway contributes to the amyloidogenic processing of APP. WHERE NEXT?: The specific inhibition of Aβ generation by SIRT1 coupled with the potential link between aerobic glycolysis, NAD(+) depletion, and amyloidogenesis through the sirtuin pathway has translational implications. On the one hand, the possible underlying role of the sirtuin pathway in Alzheimers disease onset and development might increase our understanding of this devastating condition. On the other hand, therapeutic upregulation of SIRT1 might provide opportunities for the amelioration of Alzheimers-disease-type neuropathology through inhibition of amyloidogenesis. Ultimately, further analysis into both aspects is necessary if any progress is to be made.

Abnormal Mitochondrial Dynamics—A Novel Therapeutic Target for Alzheimer's Disease?

Mitochondria are dynamic organelles that undergo continuous fission and fusion, which could affect all aspects of mitochondrial function. Mitochondrial dysfunction has been well documented in Alzheimer’s disease (AD). In the past few years, emerging evidence indicates that an imbalance of mitochondrial dynamics is involved in the pathogenesis of AD. In this review, we discuss in detail the abnormal mitochondrial dynamics in AD and how such abnormal dynamics may impact mitochondrial and neuronal function and contribute to the course of disease. Based on this discussion, we propose that mitochondrial dynamics could be a potential therapeutic target for AD.

Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease

Abstract Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimers disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxyanthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-β accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimers diseased brains, we used immunocytochemical methods to show elevated levels of 3-HK modifications and the upstream, rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO-1) in Alzheimers diseased brains when compared to controls. Importantly, the association of IDO-1 with senile plaques was confirmed and, for the first time, IDO-1 was shown to be specifically localized in conjunction with neurofibrillary tangles. As senile plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimers disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimers disease.

Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance

Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid‐β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age‐matched control cases, indicate a physiological up‐regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin‐signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD.

Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass

Considerable debate and controversy surround the cause(s) of Alzheimer’s disease (AD). To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.

Mitochondrial Dynamics in Alzheimer’s Disease

The complexities that underlie the cognitive impairment and neurodegeneration characteristic of Alzheimer’s disease (AD) have yet to be completely understood, although many factors in disease pathogenesis have been identified. Particularly important in disease development seem to be mitochondrial disturbances. As pivotal role players in cellular metabolism, mitochondria are pertinent to cell survival and thus any deviation from their operation is certainly fatal. In this review, we describe how the dynamic balance of mitochondrial fission and fusion in particular is a necessary aspect of cell proliferation and that, as the cell ages, such balance is inevitably compromised to yield a destructive environment in which the cell cannot exist. Evidence for such disturbance is abundant in AD. Specifically, the dynamic balance of fission and fusion in AD is greatly shifted toward fission, and, as a result, affected neurons contain abnormal mitochondria that are unable to meet the metabolic demands of the cell. Moreover, mitochondrial distribution in AD cells is perinuclear, with few metabolic organelles in the distal processes, where they are normally distributed in healthy cells and are needed for exocytosis, ion channel pumps, synaptic function and other activities. AD neurons are thus characterized by increases in reactive oxidative species and decreases in metabolic capability, and, notably, these changes are evident very early in AD progression. We therefore believe that oxidative stress and altered mitochondrial dynamics contribute to the precipitation of AD pathology and thus cognitive decline. These implications provide a window for therapeutic intervention (i.e. mitochondrial protection) that has the potential to significantly deter AD progression if adequately developed. Current treatment strategies under investigation are described in this review.

Pathological implications of cell cycle re-entry in Alzheimer disease

The complex neurodegeneration underlying Alzheimer disease (AD), although incompletely understood, is characterised by an aberrant re-entry into the cell cycle in neurons. Pathological evidence, in the form of cell cycle markers and regulatory proteins, suggests that cell cycle re-entry is an early event in AD, which precedes the formation of amyloid-beta plaques and neurofibrillary tangles (NFTs). Although the exact mechanisms that induce and mediate these cell cycle events in AD are not clear, significant advances have been made in further understanding the pathological role of cell cycle re-entry in AD. Importantly, recent studies indicate that cell cycle re-entry is not a consequence, but rather a cause, of neurodegeneration, suggesting that targeting of cell cycle re-entry may provide an opportunity for therapeutic intervention. Moreover, multiple inducers of cell cycle re-entry and their interactions in AD have been proposed. Here, we review the most recent advances in understanding the pathological implications of cell cycle re-entry in AD.

Review: cell cycle aberrations and neurodegeneration.

D. J. Bonda, V. P. Bajić, B. Spremo‐Potparevic, G. Casadesus, X. Zhu, M. A. Smith and H.‐G. Lee (2010) Neuropathology and Applied Neurobiology36, 157–163
Cell cycle aberrations and neurodegeneration

Dissociated amyloid-β antibody levels as a serum biomarker for the progression of Alzheimer’s disease: A population-based study

With an ever growing population of aged individuals who are at risk of developing Alzheimer disease (AD), there is an urgent need for a sensitive, specific, and preferably non-invasive diagnostic standard of disease progression. Mainstream thinking suggests that early intervention is key to maximizing the opportunity for a successful treatment regimen in AD and, as such, an early and accurate means of diagnosis is essential. In this study, we applied a recently described antibody-antigen dissociation technique to samples obtained as part of a population-based analysis of the prevalence of AD. Stratified sampling and random selection strategies were combined to obtain a representative population for screening of individuals older than 55 years. Serum antibodies to amyloid-beta (Abeta)(1-42) were measured before and after antigen dissociation. The difference between the two measurements was indicated as the dissociation delta (Delta). Our analyses showed that the levels of dissociated antibody in AD patients were always significantly different from controls and that levels of Abeta antibody after dissociation, but not those of non-dissociated antibody, correlated negatively (p<0.05) with both duration of the disease and age in the AD patients. Moreover, the change in concentration of Abeta antibody from pre- to post-dissociation (i.e., the dissociation Delta) directly reflected the progression of AD in terms of both time since diagnosis and age of the patients, with a lower dissociation Delta indicating a more advanced stage of AD. Ultimately, these data suggest that dissociated Abeta antibody levels are of significant diagnostic value at the onset of the neurodegenerative process and, thereafter, may be a useful biomarker for disease progression.