Can BACE1 Inhibition Mitigate Early Axonal Pathology in Neurological Diseases?

Abstract

β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer’s disease (AD) patients. BACE1 is being evaluated as an anti-Aβ target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development. Evidence also points to a biological role for BACE1 in axonal outgrowth and synapse formation during development. Axonal, including presynaptic, pathology exists in AD as well as many other neurological disorders such as Parkinson’s disease, epilepsy, stroke, and trauma. In this review, we discuss pharmaceutical BACE1 inhibition as a therapeutic option for axonal pathogenesis, in addition to amyloid pathology. We first introduce the amyloidogenic processing of amyloid-β protein precursor and describe the normal expression pattern of the amyloidogenic proteins in the brain, with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development, followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further elaborate the occurrence of axonal pathology in some other neurological conditions. Finally, we propose pharmacological inhibition of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders.

Lipolysaccharide-Induced Neuroinflammation Is Associated with Alzheimer-Like Amyloidogenic Axonal Pathology and Dendritic Degeneration in Rats

“…Microscopically evident axonal pathology is featured by aberrant sprouting and swelling, and increased expression of APP, BACE1 and synaptophysin, but not MAP2. These abnormal axonal profiles resemble the dystrophic neurites [61] [62], although they do not arrange in typical rosette-like clusters as seen around established compact plaques [32]. Our Golgi data indicate that focal LPS injection causes a significant decrease in dendritic length and nodes on the basal tree as well as a reduction of spine density on the entire dendritic tree of layer III cortical principal neurons.…”

“…BACE1 elevation is associated with axonal pathology during plaque development in the brains of transgenic AD models as well as aged and AD human subjects [32] [70]. As elaborated in the preceding section, we have identified axonal sprouting and swelling associated with enhanced APP, BACE1 and A β antibody reactivity in the ipsilateral cortex and hippocampal formation in LPS treated rat brains, especially evident around the needle track.…”

“…The density of dendritic spines appears to be reduced readily at prodromal stages of the disease [30]. Besides synaptic degeneration, axonal elements including presynaptic terminals undergo aberrant sprouting and dystrophic expansion [30]–[32]. Recent data from transgenic AD models, nonhuman primates and human subjects show that upregulation of the amyloidogenic proteins, especially the rate-limiting enzyme β -secretase-1 (BACE1), appears to be an molecular cascade tightly associated with axonal sprouting and dystrophy, suggestive of a driving role for amyloidogenic axonal pathology in plaque formation [33]–[35].…”

“…Neuroinflammation is considered to play an early or inductive role in the development of AD pathologies, although the anatomic evidence remains to be better formulated. Therefore, the present study was set to address whether intracerebral LPS injection in adult rats may induce axonal and dendritic pathologies similar to that seen in AD [32]. Specifically, we aimed to identify dystrophic axonal pathology inherent with amyloidogenic modulation and degenerative dendritic/spine changes on cerebral principal neurons in LPS-treated adult rats.…”

[3H]‐L685,458 Binding Sites are Abundant in Multiple Peripheral Organs in Rats: Implications for Safety Assessment of Putative γ‐Secretase Targeting Drugs

“…Double immunoflourescence was carried out to determine the expression of PS1 and Notch1. Sections were first incubated in PBS containing 5% donkey serum and 0.01% Triton X-100 for 1 hr and then reacted with rabbit anti-PS1 N-terminus (Ab14, 1:1000, courtesy of Dr S. Gandy) [5] and monoclonal mouse anti-Notch1 (N6786-200UL, 1:1000, Sigma-Aldrich-China, Shanghai, China) antibodies with gentle agitation overnight at 4°C. Next, the sections were rinsed 3 times with PBS and incubated for 2 hr with Alexa Fluor â 488-conjugated donkey anti-mouse IgG and Fluor â 594conjugated donkey anti-rabbit IgG (1:200, Invitrogen, Carlsbad, CA, USA).…”