Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease

Kang, Yeon June; Diep, Yen N.; Tran, Minh Dao; Cho, Hansang

doi:10.3390/ijms21249591

Cited by 27 publications

(22 citation statements)

References 269 publications

(225 reference statements)

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“…299 These may be pharmacological or nonpharmacological, direct or indirect interventions. [300][301][302] Among the nonpharmacological interventions, the diet and exercise are the most prominent but indirect measures. Multiple pharmacological means already exist to intervene at the neuroinflammation level such as the mentioned NSAIDs.…”

Section: Mitigatory/modulatory Treatment Of Neuroinflammationmentioning

confidence: 99%

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Fülöp¹,

Tripathi²,

Rodrigues³

et al. 2021

NDT

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Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.

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Section: Mitigatory/modulatory Treatment Of Neuroinflammationmentioning

confidence: 99%

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Fülöp¹,

Tripathi²,

Rodrigues³

et al. 2021

NDT

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“…In recent decades, many therapeutic approaches targeted the amyloid cascade components. Consequently, many clinical trials have been directed toward Aβ-lowering strategies, including interference with the amyloidogenic processing of APP, mainly with β- and γ-secretase inhibitors, and removing Aβ oligomers and plaques with monoclonal antibodies [ 22 , 27 ]. Unfortunately, until now, no therapy directed at reducing Aβ has been successful, resulting in either no cognitive benefit, or even worsening cognitive outcome or inducing major side effects [ 28 , 29 , 30 , 31 ].…”

Section: Current Strategies Targeting Ad Developmentmentioning

confidence: 99%

“…While encouraging, longer and larger trials are necessary to study the efficacy and safety of Donanemab in AD. Therapeutic strategies targeting tau are also under investigation, including inhibitors of tau kinases and tau aggregation, and immunotherapy [ 27 , 33 ]. As for Aβ-target therapies, none of the tau-targeted therapies have been successful yet, and the only treatment that has reached a phase III trial is the tau aggregation inhibitor TRx0237 (LMTX™) [ 33 ].…”

Section: Current Strategies Targeting Ad Developmentmentioning

confidence: 99%

“…Multiple promising targets to prevent AD or its progression have been identified [ 34 ]. The neuroinflammatory system, including astrocyte and microglia (key cellular regulators of neuroinflammation), and genetic variants linked to neuroinflammation, such as TREM2 , have received great attention recently due to the notable correlation between the degree of neuroinflammation and the severity of AD [ 27 , 35 , 36 ]. Targeting, APOE; a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the central nervous system, and which polymorphism is a major risk factor for developing LOAD, is also in an early phase of therapeutic development [ 17 , 19 , 37 ].…”

Section: Current Strategies Targeting Ad Developmentmentioning

confidence: 99%

“…Targeting, APOE; a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the central nervous system, and which polymorphism is a major risk factor for developing LOAD, is also in an early phase of therapeutic development [ 17 , 19 , 37 ]. Given that neurotrophin deficiency and dysregulation is closely associated with the pathogenesis of AD [ 38 ], supplementation of neurotrophic factors (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) is currently a potential therapeutic approach to treat AD [ 27 ]. Using AD animal models, this treatment has proven its efficacy to ameliorate learning deficit [ 39 , 40 ].…”

Section: Current Strategies Targeting Ad Developmentmentioning

confidence: 99%

See 2 more Smart Citations

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

Gascon

Jann

Langlois-Blais

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

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An Air Particulate Pollutant Induces Neuroinflammation and Neurodegeneration in Human Brain Models

et al. 2021

Self Cite

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Fine particulate matter (PM2.5), a major component among air pollutants, highlights as a global health concern. Several epidemiological studies show the correlation between chronical PM2.5 exposure and incidents of neurological disorders including Alzheimer's disease. However, the mechanisms have not been well understood, partly due to the lack of model systems that reflect the physiologically relevant innate immunity in human brains. Here, PM2.5‐polluted human brain models (PMBs) are created in a 3D microfluidic platform reconstituting key aspects of human brain immunity under the PM2.5 exposure. PM2.5 penetration across a blood–brain barrier (BBB) model and accumulation in the brain tissue side of the model are first validated. Second, the PMB model shows that the BBB‐penetrating PM2.5 initiates astrogliosis, resulting in slight neuronal loss and microglial infiltration. Third, it is demonstrated that the infiltrating microglia obtain M1 phenotype induced by interleukin‐1β and interferon‐γ from neurons and reactive astrocytes under the PM2.5 exposure. Finally, it is observed that additional proinflammatory mediators and nitric oxide released from the M1 microglia exacerbate neuronal damages, such as synaptic impairment, phosphoric tau accumulation, and neuronal death. This study suggests that PM2.5 can be a potential environmental risk factor for dementia mediated by the detrimental neuroinflammation.

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Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease

Cited by 27 publications

References 269 publications

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

An Air Particulate Pollutant Induces Neuroinflammation and Neurodegeneration in Human Brain Models

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