P1‐028: Overexpression of neprilysin reduces Abeta42‐induced neuron loss and intraneuronal Abeta42 deposits, but causes age‐dependent axon pathology in drosophila

Abstract

phosphorylated tau antibodies tested. Method of fixation did not reveal amyloid plaques in young 3xTg-AD mice. Plaque deposition was sex dependent with females showing more plaques than males beginning at 9 months predominately in the subiculum and to a lesser degree in the hippocampus, cortex and amygdala. Conclusions: These results stress the importance of fixation method for the immunohistochemical visualization of tau epitopes in young 3xTg-AD mice, and that intraneuronal A␤ is not necessarily a precondition for the concurrent staining of tau epitopes in select brain regions in these mutant mice. Background: The loss of the cholinergic neurons of the Nucleus Basalis of Meynert in Alzheimer's disease (AD) patients has received a lot of attention since its discovery in the early 1970s, and most presently available pharmaceutical drugs for AD are thus designed to increase the transmission of the cholinergic system. Despite this intense focus on the cholinergic system in AD the reason for the cholinergic neuron loss is yet unknown. Many mouse models of AD have been generated, but few have shown to develop neuron degeneration. Furthermore, genetically modified mouse models of AD showing loss of cholinergic neurons are scarce. APP/PS1KI mice develop a neuron loss of about 50% in the CA1 of the hippocampal formation, a characteristic also found in AD patients, as well as behavioural deficits and a severe motor pathology at the age of 6 months. This study examined A␤ induced pathology and neuron loss in the cholinergic system of the double transgenic APP/PS1KI mouse model of AD. Methods: Immunohistochemistry, stereology, real time RT-PCR. Results: Swollen ChAT positive dystrophic neurites were found in proximity of plaques especially in the motor nuclei and the striatum, as well as in the cortex, hippocampal formation and thalamus corresponding to regions innervated by the cholinergic basal forebrain and pons complexes. Expression of the APP transgene was found in ChAT positive neurons of motor nuclei accompanied by robust intracellular A␤ accumulation, however, no neurons expressing the APP transgene and thus no neurons accumulating intracellular A␤ aggregates were found in either the forebrain or pons complexes or in the caudate putamen. Stereological quantification showed a 20-30% loss of ChAT positive neurons only in the motor nuclei Mo5 and 7N at 6 and 12 months in APP/PS1KI mice, as compared to PS1KI control mice. No loss of ChAT positive neurons was found in the cholinergic forebrain complex or in the caudate putamen. Conclusions: This study reports cholinergic cell loss correlating with the accumulation of intracellular A␤ in a mouse model of AD and thus supports the hypothesis of intracellular A␤ aggregates as an early pathological alteration triggering neurodegeneration in AD. P1-

Peripheral Delivery of a CNS Targeted, Metalo-Protease Reduces Aβ Toxicity in a Mouse Model of Alzheimer's Disease

“…In addition to the effects on extracellular Aβ, NEP might modify AD-like pathology by reducing the accumulation of intracellular APP metabolites such as Aβ [22] , [23] . Increasingly, intracellular Aβ is being recognized as deleterious to the neuron as much or more than extracellular Aβ [23] , [24] , [25] .…”

“…A growing number of studies have shown that accumulation of intracellular Aβ could be deleterious[23], [24], [25], [42], [43] by triggering aberrant signaling via CREB[44]. Supporting this possibility, previous studies have shown that NEP ameliorates the deficits in the fly[22] and rodent models[23] by diminishing Aβ from the intracellular compartment. Although ApoBsecNEP was located in the soma and dendrites of neurons, it is not clear if the reduced intracellular Aβ may be driven by this source of NEP.…”

A Neuroprotective Brain-penetrating Endopeptidase Fusion Protein Ameliorates Alzheimer Disease Pathology and Restores Neurogenesis

“…Several studies have shown that intracellular A␤ could be deleterious (30, 35, 49 -51) by triggering an aberrant signaling via cAMP-response elementbinding protein (52). Supporting this possibility, previous studies have shown that neprilysin ameliorates the deficits in the fly (53) and rodent models (35) by diminishing A␤ from the intracellular compartment. Although ASN12 is primarily extracellular, it is not clear if this is capable of degrading A␤, and this shifts the equilibrium of A␤ from the intracellular space to the extracellular space, thus reducing the intracellular accumulation of A␤ indirectly.…”

Tip60 protects against amyloid-β peptide-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegenerative progression

“…Additional human AD pathologies feature learning and short-term memory (STM) loss, movement deficits, and early lethality. Each of these functional deficits is conserved in the AD-associated aged A42 model and has been previously documented and quantified (Iijima et al 2004;Iijima-Ando et al 2008;Wu et al 2019). Thus, we 7 asked whether these deficits occur during the early stages of A42-induced neuropathology and whether increasing Tip60 levels can protect against these deficits throughout neurodegenerative progression.…”