β‐Secretase‐1 elevation in aged monkey and Alzheimer’s disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and β‐amyloid accumulation

Abstract

Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly, which may relate to multiple risk factors and is pathologically featured by cerebral hypometabolism, paravascular β-amyloid (Aβ) plaques, neuritic dystrophy and intra-neuronal aggregation of phosphorylated-tau. To explore potential pathogenic link among some of these lesions, we examined β-secretase-1 (BACE1) alteration relative to Aβ deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 proteins and β-site-cleavage amyloid precursor protein Cterminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend of increased overall density among cases with greater plaque pathology. In double labeling preparations, BACE1 IR colocalized with immunolabeling for Aβ but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR coexisted with intra-axonal and extracellular Aβ IR among virtually all neuritic plaques ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype marker (GABAergic, glutamatergic, cholinergic or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near or in direct contact with blood vessels. These finds implicate that plaque formation in AD or normal aging primates relate to a multisystem axonal pathogenesis that occurs

Kamikihi-to (KKT) Rescues Axonal and Synaptic Degeneration Associated with Memory Impairment in a Mouse Model of Alzheimer's Disease, 5XFAD

“…Abnormally swollen presynaptic boutons were also reported as degenerative alterations inside and in the region around the amyloid plaques in 5XFAD cortex (Zhang et al, 2009) and aged monkey cortex (Cai et al, 2010). Similar presynaptic alteration was observed in the current study.…”

Does vascular pathology contribute to Alzheimer changes?

“…Cortical microvascular abnormalities may be impacted by ageing per se but greater degenerative changes are accelerated by amyloid deposition. Consistent with this, a recent study in rhesus monkeys [61] demonstrated that β amyloid cleaving enzyme 1 (BACE1)-labelled dystrophic axons resided near to or in direct contact with cortical blood vessels. Thus plaque formation in AD appears linked to a multisystem axonal pathogenesis occurring in partnership with potential vascular deficits (Fig.…”

BACE1 Elevation is Involved in Amyloid Plaque Development in the Triple Transgenic Model of Alzheimer’s Disease: Differential Aβ Antibody Labeling of Early-Onset Axon Terminal Pathology

“…Some Aβ antibodies may label neuronal somata and primary dendrites, although recent studies have raised concern as to whether this labeling reflects a presence of Aβ per se or other APP cleavage products [Wegiel et al, 2007; Aho et al, 2011; Gouras et al, 2010]. Notably, plaques can develop in the white matter that has few neuronal somata [Fiala, 2007; Cai et al, 2010]. Therefore, it appears that neither neuronal somata, nor dendritic, Aβ release represents an essential precondition for plaque formation.…”

“…Per this concept, we recently carried out correlative BACE1 and Aβ analysis in several transgenic models of AD (2XFAD, 5XFAD and Tg2576), demonstrating that the onset and evolution of typical neuritic plaques relate to a progressive amyloidogenic axonal pathology [Zhang et al, 2009; 2010; Cai et al, 2010]. This axonal pathology occurs initially at perisomatic axon terminals and axonal processes as distinctly labeled by the monoclonal antibody 3D6 raised against the N-terminal amino acid residues of the Aβ domain [Zhang et al, 2009].…”