Abstract
The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state.
Highlights
AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades
We demonstrated that memory deficits and cholinergic dysfunction in the hippocampus did not develop in BACE1-/-Tg2576 bigenic mice that lacked Aβ, while florid deficits were apparent in Aβ-overproducing Tg2576 monogenics
Does BACE1 initiate Aβ formation, but the observation that BACE1 levels are elevated in AD [97,166,167,168,169,170] provides a direct and compelling reason to develop therapies directed at BACE1 inhibition reducing Aβ and its associated toxicities
Summary
AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. While recent studies indicate that complete blockage of BACE1 activity may be associated with certain undesirable side-effects ( see "Putative Non-APP BACE1 Substrates" section below), important data demonstrates that in specific AD Tg models, partial reduction of BACE1 levels may improve cognitive deficits and amyloid neuropathology including Aβ deposition. In cultured polarized cells such as neurons or MadinDarby canine kidney cells, BACE1 is predominantly transported to the axonal/apical compartment, while APP and α-secretase are sorted mainly to the somatodendritic/ basolateral compartment [137] This trafficking pattern is consistent with observations in vivo indicating that BACE1 is transported down axons of the perforant pathway [138] and that axon terminals may be major sites of Aβ production [138,139]. PS : presenilin; CTF : carboxyl terminal fragment; RIP : regulated intramembrane proteolysis; DS : Down's syndrome; RNAi : RNA interference; EGF : epidermal growth factor; SAD : sporadic AD; ER : endoplasmic reticulum; ST6Gal : Beta-galactoside alpha 2,6-sialyltransferase; FAD : familial AD; TACE : TNF-α converting enzyme; GGA : Golgi-localized γ-ear containing ADP ribosylation factor-binding; GPI : glycosylphosphatidylinositol; HIF-1 : hypoxia-inducible factor 1; HMGCoA : hydroxymethylglutaryl-coenzyme A; HNE : 4hydroxy-2-nonenal; HRE : hypoxia-responsive element; ICD : intracellular domain; IL1β : interleukin β; INFγ : interferon γ; JNK : c-jun N-terminal kinases; LRP : lipoprotein receptor-related protein; TBI : traumatic brain injury; Tg : transgenic; TGN : trans Golgi network; TNFα : tumor necrosis factor α; UTR : untranslated region; VGSC : voltage-gated sodium channel
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