The Latest Articles on Alzheimer's Disease

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on Alzheimer's disease.

Title: Putative pathological mechanisms of late-life depression and Alzheimer.s Disease
Authors: S.M. Nageeb Hasan, Courtney Leigh Clarke, Tadhg Patrick McManamon Strand, Francis Rodriguez Bambico
Type: Review
Abstract:
Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive impairment in cognition and memory. AD is accompanied by several neuropsychiatric symptoms, with depression being the most prominent. Although depression has long been known to be associated with AD, controversial findings from preclinical and clinical studies have obscured the precise nature of this association. However recent evidence suggests that depression could be a prodrome or harbinger of AD. Evidence indicates that the major central serotonergic nucleus–the dorsal raphe nucleus (DRN)–shows very early AD pathology: neurofibrillary tangles made of hyperphosphorylated tau protein and degenerated neurites. AD and depression share common pathophysiologies, including functional deficits of the serotonin (5-HT) system. 5-HT receptors have modulatory effects on the progression of AD pathology i.e., reduction in Aβ load, increased hyper-phosphorylation of tau, decreased oxidative stress etc. Moreover, preclinical models show a role for specific channelopathies that result in abnormal regional activational and neuroplasticity patterns. One of these concerns the pathological upregulation of the small conductance calcium-activated potassium (SK) channel in corticolimbic structure. This has also been observed in the DRN in both diseases. The SKC is a key regulator of cell excitability and long-term potentiation (LTP). SKC over-expression is positively correlated with aging and cognitive decline, and is evident in AD. Pharmacological blockade of SKCs has been reported to reverse symptoms of depression and AD. Thus, aberrant SKC functioning could be related to depression pathophysiology and diverts its late-life progression towards the development of AD. We summarize findings from preclinical and clinical studies suggesting a molecular linkage between depression and AD pathology. We also provide a rationale for considering SKCs as a novel pharmacological target for the treatment of AD-associated symptoms.
Access this article: https://doi.org/10.1016/j.brainres.2023.148423

Title: Emerging concepts towards a translational framework in Alzheimer's disease
Authors: Danielle Cozachenco, Eduardo R. Zimmer, Mychael V. Lourenco
Type: Review
Abstract:
Over the past decades, significant efforts have been made to understand the precise mechanisms underlying the pathogenesis of Alzheimer's disease (AD), the most common cause of dementia. However, clinical trials targeting AD pathological hallmarks have consistently failed. Refinement of AD conceptualization, modeling, and assessment is key to developing successful therapies. Here, we review critical findings and discuss emerging ideas to integrate molecular mechanisms and clinical approaches in AD. We further propose a refined workflow for animal studies incorporating multimodal biomarkers used in clinical studies – delineating critical paths for drug discovery and translation. Addressing unresolved questions with the proposed conceptual and experimental framework may accelerate the development of effective disease-modifying strategies for AD.
Access this article: https://doi.org/10.1016/j.neubiorev.2023.105246

Title: An Approach for In-Situ Detection of Gold Colloid Aggregates Amyloid Formations Within The Hippocampus of The Cohen's Alzheimer's Disease Rat Model By Surface Enhanced Raman Scattering Methods
Authors: Kazushige Yokoyama, Joshua Thomas, Windsor Ardner, Madison Kieft, Lorenz S. Neuwirth, Wei Liu
Type: Research Article
Abstract:

Background
Amyloid beta (Aβ) peptides, such as Aβ1-40 or Aβ1-42 are regarded as hallmark neuropathological biomarkers associated with Alzheimer's disease (AD). The formation of an aggregates by Aβ1-40 or Aβ1-42-coated gold nano-particles are hypothesized to contain conformation of Aβ oligomers, which could exist only at an initial stage of fibrillogenesis.

New Method
The attempt of in-situ detection of externally initiated gold colloid (ca. 80 nm diameter) aggregates in the middle section of the hippocampus of the Long Evans Cohen's Alzheimer's disease rat model was conducted through the Surface Enhanced Raman Scattering (SERS) method.

Results
The SERS spectral features contained modes associated with β-sheet interactions and a significant number of modes that were previously reported in SERS shifts for Alzheimer diseased rodent and human brain tissues; thereby, strongly implying a containment of amyloid fibrils. The spectral patterns were further examined and compared with those collected from in-vitro gold colloid aggregates which were formed from Aβ1-40 - or Aβ1-42 -coated 80 nm gold colloid under pH ~4, pH ~7, and pH ~10, and the best matched datasets were found with that of the aggregates of Aβ1-42 -coated 80 nm gold colloid at ~pH 4.0. The morphology and physical size of this specific gold colloid aggregate was clearly different from those found in-vitro.

Comparison with Existing Method(s)
The amyloid fibril with a β-sheet conformation identified in previously reported in AD mouse/human brain tissues was involved in a formation of the gold colloid aggregates. However, to our surprise, best explanation for the observed SERS spectral features was possible with those in vitro Aβ1-42 -coated 80 nm gold colloid under pH ~4.

Conclusions
A formation of gold colloid aggregates was confirmed in the AD rat hippocampal brain section with unique physical morphology compared to those observed in in-vitro Aβ1-42 or Aβ1-40 mediated gold colloid aggregates. It was concluded that a β-sheet conformation identified in previously reported in AD mouse/human brain tissues was in volved in a formation of the gold colloid aggregates.

Title: Functional effects of gut microbiota-derived metabolites in Alzheimer's disease
Authors: Hyunjung Choi, Inhee Mook-Jung
Type: Review
Abstract:
The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aβ and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.
Access this article: https://doi.org/10.1016/j.conb.2023.102730

Title: Spectral power ratio as a measure of EEG changes in mild cognitive impairment due to Alzheimer's disease: a case-control study
Authors: Aimee A. Flores-Sandoval, Paula Davila-Pérez, Stephanie S. Buss, Kevin Donohoe, Margaret O' Connor, Mouhsin M. Shafi, Alvaro Pascual-Leone, Christopher S.Y. Benwell, Peter J. Fried
Type: Research Article
Abstract:
Adopting preventive strategies in individuals with subclinical Alzheimer's disease (AD) has the potential to delay dementia onset and reduce health care costs. Thus, it is extremely important to identify inexpensive, scalable, sensitive, and specific markers to track disease progression. The electroencephalography spectral power ratio (SPR: the fast to slow spectral power ratio), a measure of the shift in power distribution from higher to lower frequencies, holds potential for aiding clinical practice. The SPR is altered in patients with AD, correlates with cognitive functions, and can be easily implemented in clinical settings. However, whether the SPR is sensitive to pathophysiological changes in the prodromal stage of AD is unclear. We explored the SPR of individuals diagnosed with amyloid-positive amnestic mild cognitive impairment (Aβ+aMCI) and its association with both cognitive function and amyloid load. The SPR was lower in Aβ+aMCI than in the cognitively unimpaired (CU) individuals and correlated with executive function scores but not with amyloid load. Hypothesis generating analyses suggested that aMCI participants with a lower SPR had an increased probability of a positive amyloid PET. Future research may explore the potential of this measure to classify aMCI individuals according to their AD biomarker status.
Access this article: https://doi.org/10.1016/j.neurobiolaging.2023.05.010