Mark A. Smith

The human β-defensins (hBDs) are a highly conserved family of cationic antimicrobial and immunomodulatory peptides expressed primarily by epithelial cells in response to invasion by bacteria, fungi and some viruses. To date, the most studied members of this family of peptides are hBD-1, -2, and -3. Expression of hBD-1 and -2 has been demonstrated previously in cultured microglia and astrocytes of both mouse and human brain. Unlike inducible hBD-2 and -3, hBD-1 is constitutively expressed and is not generally upregulated by proinflammatory factors. In this study, we investigated whether hBDs, as active components of the innate immune response, are affected by pathological events in the Alzheimer’s disease (AD) brain. We assessed the expression of hBD-1, -2, and -3 in tissue obtained at autopsy from AD and age-matched control brains.

Introduction: Heterogeneity in risk of conversion to Alzheimer's disease (AD) among individualswith mild cognitive impairment (MCI) is well known. Novel statistical methods thatare based on partially ordered set (poset) models can be used to create modelsthat provide detailed and accurate information about performance with specificcognitive functions. This approach allows for the study of direct links betweenspecific cognitive functions and risk of conversion to AD from MCI. It also allowsfor further delineation of multi-domain amnestic MCI, in relation to specificnon-amnestic cognitive deficits, and the modeling of a range of episodic memoryfunctioning levels. Methods: From the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, conversion at24 months of 268 MCI subjects was analyzed. It was found that 101 of thosesubjects (37.7%) converted to AD within that time frame. Poset models were thenused to classify cognitive performance for MCI subjects. Respective observedconversion rates to AD were calculated for various cognitive subgroups, and byAPOE e4 allele status. These rates were then compared across subgroups. Results: The observed conversion rate for MCI subjects with a relatively lower functioningwith a high level of episodic memory at baseline was 61.2%. In MCI subjects whoadditionally also had relatively lower perceptual motor speed functioning and atleast one APOE e4 allele, the conversion rate was 84.2%. In contrast, the observedconversion rate was 9.8% for MCI subjects with a relatively higher episodic memoryfunctioning level and no APOE e4 allele. Relatively lower functioning withcognitive flexibility and perceptual motor speed by itself also appears to beassociated with higher conversion rates. Conclusions: Among MCI subjects, specific baseline cognitive profiles that were derived throughposet modeling methods, are clearly associated with differential rates ofconversion to AD. More precise delineation of MCI by such cognitive functioningprofiles, including notions such as multidomain amnestic MCI, can help in gainingfurther insight into how heterogeneity arises in outcomes. Poset-based modelingmethods may be useful for providing more precise classification of cognitivesubgroups among MCI for imaging and genetics studies, and for developing moreefficient and focused cognitive test batteries.

CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson’s disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3ζ in association with the α-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson’s disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain. Owing to the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase in AD, emphasizing the importance of disease-altering therapy. Current therapeutics on the market, including cholinesterase inhibitors and N-methyl-_D-aspartate receptor antagonists, provide symptomatic relief but do not alter progression of the disease. Therefore, progress in the areas of prevention and disease modification may be of critical interest. In this review, we summarize novel AD therapeutics that are currently being explored, and also mechanisms of action of specific drugs within the context of current knowledge of AD pathologic pathways.

Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's 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 Alzheimer's 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 Alzheimer's 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 Alzheimer's disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimer's 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-β 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.