A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment

Abstract

Alzheimer's disease (AD), the most common cause of age-dependent dementia, is one of the most significant healthcare problems worldwide. Aggravating this situation, drugs that are currently US Food and Drug Administration (FDA)-approved for AD treatment do not prevent or delay disease progression. Therefore, developing effective therapies for AD patients is of critical urgency. Human genetic and clinical studies over the past three decades have indicated that abnormal generation or accumulation of amyloid-β (Aβ) peptides is a likely culprit in AD pathogenesis. Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1) (memapsin 2, β-secretase, Asp 2 protease) and γ-secretase. Mice deficient in BACE1 show abrogated production of Aβ. Therefore, pharmacological inhibition of BACE1 is being intensively pursued as a therapeutic approach to treat AD patients. Recent setbacks in clinical trials with BACE1 inhibitors have highlighted the critical importance of understanding how to properly inhibit BACE1 to treat AD patients. This review summarizes the recent studies on the role of BACE1 in synaptic functions as well as our views on BACE1 inhibition as an effective AD treatment.

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

“…Moreover, T2D per se is associated with cognitive dysfunction that can range from subtle diabetes-associated cognitive decrements to pre-dementia and dementia [4]. On the other hand, AD has no successful treatment, and therapeutic efforts have been directed towards classical neuropathological features that include gamma-secretase modulators, BACE1 inhibitors, immunotherapy, or taubased therapies [5][6][7]. However, different limitations have been raised [8] reducing the presently approved treatments to acetylcholinesterase inhibitors and glutamate antagonist memantine [9].…”

Acetylcholinesterase: The “Hub” for Neurodegenerative Diseases and Chemical Weapons Convention

“…Galantamine acts simultaneously as an AChE inhibitor and allosteric modulator of nicotinic receptors, increasing the affinity for ACh [114][115][116][117][118][119][120][121][122][123][124][125][126][127][128]. Research in progress on novel AD drugs has covered different disciplines and been focused on further development of AChE inhibitors, beta-secretase 1 (BACE-1) inhibitors, serotonin 5-HT4 receptor inhibitors and PROTAC (PROteolysis Targeting Chimeras) compounds, among other approaches [129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146]. Rivastigmine is regarded to react with the serine residue of the ES present in AChE and BChE (as shown in Scheme 3), whereas donepezil can act in both CAS and PAS of AChE.…”

NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

“…Blood samples for pharmacokinetic (PK) assessments were taken at a time before drug administration and at scheduled times after dosing, specifically at 0.25, 0.5, 1, 1.5, 2, 3,4,5,6,8,10,12,18,24,36,48,72,96, and 144 hours after dose for Phase 1a. For Phase 1b, days 1 and 14: 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours after dose and at 5 hours after dose for days 2 to 13.…”

“…Treatment of AD has focused on the amyloid cascade hypothesis [13,14] and led to studies focused on prevention of the damaging effects of Ab 42 , the hallmark peptide in amyloid plaques [4,15,16]. Multiple small molecule and biological approaches targeting the Ab 42 peptide resulted in many failures because most of these agents had limited efficacy and significant side effects, particularly when inhibiting the enzymes that cleave the amyloid precursor protein resulting in amyloid-b (Ab) peptide liberation [16][17][18][19][20][21]. An alternative approach to the use of molecules that fully inhibit enzyme activity is to use modulators of the gamma secretase complex (GSMs) which selectively lower Ab 42 and raise the levels of shorter Ab peptides [22][23][24][25][26][27].…”