The Time Course of Recognition Memory Impairment and Glial Pathology in the hAPP-J20 Mouse Model of Alzheimer’s Disease

Abstract

The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer's disease. The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of A .Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 hrs). Immunohistochemistry was used to characterise A -deposition, and quantify astrocyte and microglial responses. At all ages tested J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localisation of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types.This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of A and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression.

Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer’s Disease

“…Using a chronic mouse preparation, previous research from our laboratory found no significant neurovascular deficits in the J20-hAPP mouse between 9-12m age 9 , despite neuroinflammation and memory deficits 5 . This is contrary to what other laboratories have shown with the J20-mouse at the same age 10-12 .…”

“…Amyloid plaques are a key pathological hallmark of AD and begin to form in the hippocampus in the J20-hAPP AD mouse at around 6m of age 5 . The progression of plaque pathology and subsequent inflammatory changes have been well characterised in the J20-AD mouse 5 .…”

“…The J20-hAPP mouse model of AD over-expresses human amyloid precursor protein (hAPP) with the Swedish (K670N and M671L) and the Indiana (V7171F) familial mutations 4 . These mice produce more Aβ1-42 and plaques begin to readily form in the hippocampus from around 5-6 months of age 4,5 . The J20-hAPP mouse model displays significant neuroinflammation characterised by gliosis of both astrocytes and microglia 5 .…”

“…These mice produce more Aβ1-42 and plaques begin to readily form in the hippocampus from around 5-6 months of age 4,5 . The J20-hAPP mouse model displays significant neuroinflammation characterised by gliosis of both astrocytes and microglia 5 . They also display significant longterm memory impairment 5 .…”

“…The J20-hAPP mouse model displays significant neuroinflammation characterised by gliosis of both astrocytes and microglia 5 . They also display significant longterm memory impairment 5 . The brain is extremely metabolically demanding, and the neurophysiological process of neurovascular coupling ensures that neurons receive an efficient and adequate blood supply to match the metabolic demands that neurons exert.…”