BACKGROUND: β-Amyloid (Aβ) plaques are a pathological hallmark of Alzheimer's disease (AD) and multiple lines of evidence have linked Aβ with AD. However, synapse loss is known as the best pathological correlate of cognitive impairment in AD, and intraneuronal Aβ accumulation has been shown to precede plaque pathology. The progression of Aβ accumulation to synapse loss and plaque formation remains incomplete. The objective is to investigate the progression of intraneuronal Aβ accumulation in the brain. METHODS: To visualize and analyze the development of Aβ pathology we perform immunohistochemistry and immunofluorescence microscopy using antibodies against different Aβ conformations, synaptic proteins and structural neuronal proteins in brain tissue of AD transgenic mouse models. RESULTS: Our results show the intraneuronal onset of Aβ42 accumulation in AD mouse brains with aging. We observe an inverse correlation of Aβ and amyloid fibrils with structural proteins within neurites. Images reveal aggregated amyloid within selective pyramidal neurons, neurites and synapses in AD transgenic mice as plaques arise. CONCLUSION: The data support that Aβ42 accumulation and aggregation begin within AD-vulnerable neurons in the brain. Progressive intraneuronal Aβ42 aggregation disrupts the normal cytoarchitecture of neurites.
BACKGROUND: β-Amyloid (Aβ) plaques are a pathological hallmark of Alzheimer's disease (AD) and multiple lines of evidence have linked Aβ with AD. However, synapse loss is known as the best pathological correlate of cognitive impairment in AD, and intraneuronal Aβ accumulation has been shown to precede plaque pathology. The progression of Aβ accumulation to synapse loss and plaque formation remains incomplete. The objective is to investigate the progression of intraneuronal Aβ accumulation in the brain. METHODS: To visualize and analyze the development of Aβ pathology we perform immunohistochemistry and immunofluorescence microscopy using antibodies against different Aβ conformations, synaptic proteins and structural neuronal proteins in brain tissue of ADtransgenicmouse models. RESULTS: Our results show the intraneuronal onset of Aβ42 accumulation in ADmouse brains with aging. We observe an inverse correlation of Aβ and amyloid fibrils with structural proteins within neurites. Images reveal aggregated amyloid within selective pyramidal neurons, neurites and synapses in ADtransgenic mice as plaques arise. CONCLUSION: The data support that Aβ42 accumulation and aggregation begin within AD-vulnerable neurons in the brain. Progressive intraneuronal Aβ42 aggregation disrupts the normal cytoarchitecture of neurites.
Authors: John W Steele; Hannah Brautigam; Jennifer A Short; Allison Sowa; Mengxi Shi; Aniruddha Yadav; Christina M Weaver; David Westaway; Paul E Fraser; Peter H St George-Hyslop; Sam Gandy; Patrick R Hof; Dara L Dickstein Journal: J Comp Neurol Date: 2014-07-01 Impact factor: 3.215