Toward the Treatment and Prevention of Alzheimer's Disease: Rational Strategies and Recent Progress

Alzheimer’s disease (AD) is one of the most frequently diagnosed types of dementia in the elderly. An important pathological feature in AD is the aggregation and deposition of the β-amyloid (Aβ) in extracellular plaques. Transthyretin (TTR) can cleave Aβ, resulting in the formation of short peptides with less activity of amyloid plaques formation, as well as being able to degrade Aβ peptides that have already been aggregated. In the presence of TTR, Aβ aggregation decreases and toxicity of Aβ is abolished. This may prevent amyloidosis but the malfunction of this process leads to the development of AD. In the context of Aβplaque formation in AD, we discuss metallothionein (MT) interaction with TTR, the effects of which depend on the type of MT isoform. In the brains of patients with AD, the loss of MT-3 occurs. On the contrary, MT-1/2 level has been consistently reported to be increased. Through interaction with TTR, MT-2 reduces the ability of TTR to bind to Aβ, while MT-3 causes the opposite effect. It increases TTR-Aβ binding, providing inhibition of Aβ aggregation. The protective effect, assigned to MT-3 against the deposition of Aβ, relies also on this mechanism. Additionally, both Zn7MT-2 and Zn7MT-3, decrease Aβ neurotoxicity in cultured cortical neurons probably because of a metal swap between Zn7MT and Cu(II)Aβ. Understanding the molecular mechanism of metals transfer between MT and other proteins as well as cognition of the significance of TTR interaction with different MT isoforms can help in AD treatment and prevention.

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Elucidation of Mechanism Underlying Amyloid-β Peptide Aggregation and Its Neurotoxicity Expression and Inhibition of These Molecular Processes by Beneficial Synthetic and Natural Compounds with Low-molecular Weights—New Approaches to Fundamental Treatment and Prevention of Alzheimer's Disease—

YAKUGAKU ZASSHI ◽

10.1248/yakushi.130.493 ◽

2010 ◽

Vol 130 (4) ◽

pp. 493-494

Author(s):

Tohru YAMAKUNI

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Natural Compounds ◽

Amyloid Β Peptide ◽

Peptide Aggregation ◽

Molecular Processes ◽

Molecular Weights ◽

New Approaches ◽

Treatment And Prevention

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Recent Progress in the Identification of Non-Invasive Biomarkers to Support the Diagnosis of Alzheimer’s Disease in Clinical Practice and to Assist Human Clinical Trials

Alzheimer's Disease - Challenges for the Future ◽

10.5772/60008 ◽

2015 ◽

Author(s):

Francois Bernier ◽

Pavan Kumar ◽

Yoshiaki Sato ◽

Yoshiya Oda

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Clinical Practice ◽

Recent Progress ◽

Non Invasive

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PRECISION MEDICINE - THE GOLDEN GATE FOR DETECTION, TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2016.112 ◽

2016 ◽

pp. 1-17

Author(s):

H. Hampel ◽

S.E. O’Bryant ◽

J.I. Castrillo ◽

C. Ritchie ◽

K. Rojkova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Precision Medicine ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

Late Onset ◽

Therapeutic Success ◽

Preclinical Stage ◽

Treatment And Prevention

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

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Science Runs and the Debate Brakes: Somatic Gene-Editing as a New Tool for Gender-Specific Medicine in Alzheimer’s Disease

Brain Sciences ◽

10.3390/brainsci10070421 ◽

2020 ◽

Vol 10 (7) ◽

pp. 421 ◽

Cited By ~ 2

Author(s):

Pamela Tozzo ◽

Silvia Zullo ◽

Luciana Caenazzo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gender Equity ◽

Gene Editing ◽

Gender Diversity ◽

Sex And Gender ◽

Treatment And Prevention ◽

Genetic Level ◽

And Gender ◽

Gender Specific

Gender-specific medicine is a discipline that studies the influence of sex and gender on physiology, pathophysiology, and diseases. One example in light of how a genetic-based disease among other diseases, that impact on sex, can be represented by the risk of developing dementia or Alzheimer’s disease. The question that comes into focus is whether gene-editing can represent a new line of investigation to be explored in the development of personalized, gender-specific medicine that guarantees gender equity in health policies. This article aims to discuss the relevance of adopting a gender-specific focus on gene-editing research, considered as a way of contributing to the advance of medicine’s understanding, treatment, and prevention of dementia, particularly Alzheimer’s disease. The development or improvement of cures could take advantage of the knowledge of the gender diversity in order to ascertain and develop differential interventions also at the genetic level between women and men, and this deserves special attention and deep ethical reflection.

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