Can brain impermeable BACE1 inhibitors serve as anti-CAA medicine?

Abstract

BackgroundCerebral amyloid angiopathy (CAA) is characterized by the deposition of ß-amyloid peptides (Aß) in and surrounding the wall of microvasculature in the central nervous system, together with parenchymal amyloid plaques collectively referred to as cerebral amyloidosis, which occurs in the brain commonly among the elderly and more frequently in patients with Alzheimer’s disease (AD). CAA is associated with vascular injury and may cause devastating neurological outcomes. No therapeutic approach is available for this lesion to date.Main bodyß-Secretase 1 (BACE1) is the enzyme initiating Aß production. Brain permeable BACE1 inhibitors targeting primarily at the parenchymal plaque pathology are currently evaluated in clinical trials. This article presents findings in support of a role of BACE1 elevation in the development of CAA, in addition to plaque pathogenesis. The rationale, feasibility, benefit and strategic issues for developing BACE1 inhibitors against CAA are discussed. Brain impermeable compounds are considered preferable as they might exhibit sufficient anti-CAA efficacy without causing significant neuronal/synaptic side effects.ConclusionEarly pharmacological intervention to the pathogenesis of CAA is expected to provide significant protection for cerebral vascular health and hence brain health. Brain impermeable BACE1 inhibitors should be optimized and tested as potential anti-CAA therapeutics.

Lack of human-like extracellular sortilin neuropathology in transgenic Alzheimer’s disease model mice and macaques

“…The triple-transgenic mouse model of AD (3×Tg-AD) also harbors a mutant human tau (P301L) gene associated with frontotemporal dementia [ 7 ] and develops both plaque- and tangle-like pathologies in the brain [ 8 ]. Transgenic AD models are widely used in exploratory studies and have provided insights into the biological, pathogenic, and behavioral/cognitive underpinnings of this disease [ 2 , 3 , 9 , 10 ]. These animal models have also served as a prime system for the development and evaluation of various AD therapeutic approaches [ 1 , 11 , 12 ].…”

Neurovascular unit dysfunction in Alzheimer’s disease

“…Finally, the increase in Aβ accumulation (hit two) accelerates neuronal dysfunction, NFT formation, neurodegeneration, and dementia [29] (Figure 3, step 4). [117]. [118] Verubecestat/NCT01739348 ¥ III [119] Umibecestat/NCT01097096 ¥ III [120] LY2886721/NCT01561430 ¥ III [121] (b) Gamma-secretase inhibitors and modulators Semagacestat/NCT00594568 ¥ III Effect on NVU cells.…”