The Role Of Dystrophic Axons In The Process Of Senile Plaques Formation In Transgenic Mouse Models Of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly and its prevalence increases with age. The neuronal degeneration in the cerebrum, especially in hippocampus and neocortex. is the main pathology. The presence of neuritic plaques or senile plaques (SP) is one of the most important pathological hallmarks of AD, which are composed of extracellularβ-amyloid peptide (Aβ) deposits and dystrophic neurites. However, the origin of extracellular Aβdeposits and the process of plaque development remain poorly understood. The amyloid cascade hypothesis posits that Aβaccumulation plays a causal role in AD pathogenesis and demonetia, although it has been challenged by many more recent findings in the field. BACE1 is the key enzyme and rate-limiting enzyme in the process of Aβformation from APP and elevates in the brains of AD patients and transgenic mice. We attempted to explore mechanism of plaque development using transgenic mice ad models by examining the relationship between the process of plaque formation and axonal pathology.Objective:To explore ifβ-secretase-1 (BACE1) elevates with age in transgenic mice harboring familial AD (FAD) mutations (5XFAD and 2XFAD); to investigate the relationship between BACE1 and Aβaccumulation; to see if BACE1 elevation is related to neuritic alterations; and to explore the possible mechanism for amyloid plaque formation. Methods:1. 5XFAD mice were examined at postnatal day 30-45 and 2,3,4,6 and 8 months,2XFAD mice were examined at 6,9,12and 18 months to investigate the levels of BACE1 protein, (3-site APP cleavage andβ-amyloid. C57BL/6L mice were batch-processed with transgenic counterparts at matched age points.2. Immunohistochemistry was used to investigate the relationship between BACEl andβ-amyloid deposition and neuritic alterations and to observe the occurrence and development of the plaques at different time points.3. A comparative densitometric analysis was used to determine BACE1/Aβimmunoreactivity with plaque-associated and pre-plaque dystrophic axons at selected ages. Results:1. The levels of BACE1 protein, (3-site APP cleavage and P-amyloid are elevated with in transgenic mice relative to non-transgenic mice.2. Locally elevated BACE1 immunoreactivity (ir) coexisted with compact-like AP deposition, with BACE1 ir occurring selectively in dystrophic axons of various neuronal phenotypes or origins (GABAergic, glutamatergic, cholinergic or catecholaminergic).3. Prior to plaque onset, localized BACE1/Aβ-ir occurred at swollen presynaptic terminals and fine axonal processes. Conclusions:1. These data suggest that BACE1 elevation and associated Aβoverproduction inside the sprouting/dystrophic axonal terminals coincide with the onset and accumulation of extracellular amyloid deposition during the development of neuritic plaques in transgenic models of AD.2. Axonal pathogenesis plays a key or leading role in plaque formation.3. These BACEl/Aβ-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Aβir emerged and accumulated in surrounding extracellular space.