Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

Elmaleh, David R.; Farlow, Martin R.; Conti, Peter S.; Tompkins, Ronald G.; Kundakovic, Ljiljana; Tanzi, Rudolph E.

doi:10.3233/jad-190507

Cited by 108 publications

(88 citation statements)

References 96 publications

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“…The production and maturation of BDNF in the brain is regulated by Cu 2+ -dependent metalloproteinases. In SHSY5Y cells, Cu 2+ treatment decreased pro-BDNF level in cells and increased pro-and mature BDNF levels in the medium [128] with a strong decrease of the proliferative activity of both cleaved BDNF (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and the full length protein [129]. Application of zinc chelator induced reduction of BDNF level, synaptic plasticity-related proteins and dendritic spine density in vivo, which further confirm that appropriate amount of Zn 2+ is essential in brain development and the synaptic functions [130].…”

Section: Zincmentioning

confidence: 54%

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Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

295

188

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Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

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Section: Zincmentioning

confidence: 54%

“…Several gene mutations on APP and presenilin (PS1 and PS2, the γ-secretases) have been identified to promote Aβ production. Furthermore, aggregation of Aβ could form oligomers and plaques, and the oligomers are recognized as the more toxic form of Aβ [3,4].…”

Section: Introductionmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

295

188

View full text Add to dashboard Cite

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“…Furthermore, current immunotherapeutic approaches in human clinical trials are associated with adverse occurrence of amyloid related imaging abnormalities (ARIA). These complications are linked to rapid clearance of CAA, resulting in blood-barrier breakdown and excessive neuroinflammation (Wisniewski and Goñi, 2015;Herline et al, 2018;Elmaleh et al, 2019). Hence, the SQM represents an essential model for testing immunomodulatory approaches for neurodegenerative disorders due to its accurate mimicry of human CAA that could potentially lead to development of ARIA, and by having an immune system much more proximate to humans (Heuer et al, 2012(Heuer et al, , 2017Drummond and Wisniewski, 2017).…”

Section: Discussionmentioning

confidence: 99%

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

Nehete

Williams

Chitta

et al. 2020

Front. Aging Neurosci.

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One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.

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“…Debido a la importancia de esta enfermedad, en numerosos ensayos clínicos se han explorado agentes que podrían no sólo interferir con la fisiología de la enfermedad sino también proporcionar una mejora sintomática a corto plazo. Sin embargo, hasta la fecha ninguno de los tratamientos modificadores de la EA ha alcanzado la aprobación regulatoria (Elmaleh et al, 2019)…”

Section: Figura 2: Aunclassified

“…Pese a todos los esfuerzos aún no se observan terapias efectivas, se han realizado más de 400 pruebas de más de 200 fármacos con una tasa de fracaso del 99,6% (tasa de éxito de sólo el 0,4%) (Elmaleh et al, 2019). Posiblemente este efecto tan limitado se deba a una intervención demasiado tardía.…”

Section: Figura 2: Aunclassified

Estudio teórico de SFRP1 como nueva diana terapéutica para el tratamiento del Alzheimer

Rubio¹,

Carrión²,

Río³

et al. 2020

DIANAS

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Palabras clave: enfermedad de Alzheimer; SFRP1; ADAM10; drug discovery project Resumen La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa del sistema nervioso central caracterizada por una muerte progresiva neuronal que afecta principalmente a regiones corticales del cerebro y parte del sistema límbico. Se producen alteraciones en la memoria, el lenguaje, la percepción, la orientación y las funciones ejecutivas, siendo una de las principales causas de demencia en el mundo. Una de las principales características de la EA es la aparición de placas seniles o amiloides. Las placas seniles son depósitos extra-neuronales conformados por la acumulación del péptido Aβ-42 (péptido βamiloide), producido por la proteólisis de la proteína precursora amiloide (APP) por β-secretasa y γsecretasa. En cambio, la escisión no patológica de APP se produce por α-secretasa y γ-secretasa. Se prevé que la EA afecte a más de 150 millones de personas para 2050, convirtiéndose en un problema socioeconómico grave. Pese a todos los esfuerzos, aún no se ha conseguido ninguna terapia efectiva. Debido a la ineficacia en las terapias contra las dianas terapéuticas conocidas actualmente, en el presente trabajo hemos investigado la proteína SFRP1 como una nueva diana terapéutica potencial. SFRP1 se encuentra sobre-expresada en pacientes con EA produciendo inhibición de ADAM10 (αsecretasa), favoreciendo la formación del péptido β-amiloide. Hemos desarrollado, de forma teórica, un proyecto para conseguir compuestos que inhiban SFRP1 e impidan su unión a ADAM10, de forma que esta α-secretasa pueda realizar su función. Para este proyecto teórico asumimos que disponemos de una librería con numerosos compuestos químicos a partir de la cual diseñamos un proceso de drug discovery con el objetivo de conseguir un compuesto con capacidad de inhibir a SFRP1 cuyas propiedades permitan su uso como fármaco. Para ello hemos desarrollado un pre-cribado computacional y un posterior ensayo de alto rendimiento (HTS) mediante FRET. Este ensayo nos permitiría identificar qué compuestos cuentan con un mayor porcentaje de inhibición y serían re-evaluados con ensayos HTS para seleccionar aquellos con menor IC-50 y mayor selectividad frente a SFRP1. A continuación, se evaluarán mediante un ensayo PAMPA los compuestos con capacidad para atravesar la barrera hematoencefálica y se realizarán estudios in vitro en células telencefálicas e in vivo en modelos de murinos de EA para confirmar su eficacia. Por último, se desarrollarían estudios pre-clínicos de farmacología y toxicología de los compuestos seleccionados, como paso previo al estudio del fármaco en ensayos clínicos para comprobar si finalmente podría usarse como tratamiento de la EA.

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Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

Cited by 108 publications

References 96 publications

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis)

Estudio teórico de SFRP1 como nueva diana terapéutica para el tratamiento del Alzheimer

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