Abstract
SummaryAlzheimer’s disease (AD) is a chronic neurodegenerative disease that mainly causes dementia. It is a serious threat to the health of the global elderly population. Considerable money and effort has been invested in the development of drug therapy for AD worldwide. Many drug therapies are currently under development or in clinical trials, based on two known mechanisms of AD, namely, Aβ toxicity and the abnormal Tau hyperphosphorylation. Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation, neurotransmitter imbalance, oxidative damage and mitochondrial dysfunction, neuron loss and degeneration. Even so, the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited. However, multi-drug combinations may provide a new avenue for drug therapy for AD. In addition, early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.
Highlights
In view of the urgent need of drugs for the treatment of Alzheimer’s disease (AD), here, we review the progress of drug therapies for AD related to tau lesions and Aβ toxicity, and other AD pathological changes
TPI-287 was tried in humans and it was intravenously injected into patients with mild to moderate AD in a phase 1/2 clinical trial, the results showed that the drug was not well tolerated by patients as severe hypersensitivity reactions were observed[54]. 2.4 Inhibition of P-Tau Aggregation
A large amount of money and energy has been invested in the research and development of therapeutic drugs for AD, it is unfortunate to find out that many of the disease modifying treatment (DMT) drugs fail in clinical trials due to safety and/or effectiveness problems
Summary
Amyloid beta (Aβ) is mainly formed by the cleavage of amyloid precursor protein (APP). Up-regulating α-secretase, inhibiting β- secretase and γ-secretase, as well as reducing APP production and promoting Aβ clearance are the main strategies for AD drug research and development aiming at Aβ toxicity. BACE1 can promote APP cleavage to produce Aβ, and preventing this process may reduce the production and the subsequent deposition of Aβ. A recent phase 3 clinical trial of Aducanumab in patients with mild AD did not significantly improve cognitive impairment[29] This failure was speculated to be due to the fact that the pathological changes of the recruited AD patients at the beginning of the trial are so severe that Aducanumab cannot reverse them[29]. Other Aβ scavenging agents such as Thiethylperazine (antiemetic; activated transporter ABCC1) and Efavirenz (non-nucleoside reverse transcriptase inhibitor) are in clinical trials[25]
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