Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network

Abstract

Recent studies using animal models indicated that the members of the amyloid precursor protein (APP) gene family are important for the formation, maintenance, and plasticity of synapses. Despite this, the specific role of the APP homologs APLP1 and APLP2 within the CNS and PNS is still poorly understood. In contrast to the subtle phenotypes of single mutants, double knockout mice (DKO) lacking APP/APLP2 or APLP1/APLP2 die within the first day after birth. Whereas APP/APLP2-DKO mice show severe deficits of neuromuscular morphology and transmission, the underlying cause of lethality of APLP1/APLP2-DKO mice remains unclear. Since expression of both proteins was confirmed by in situ hybridization, we aimed to test the role of APLP1/APLP2 in the formation and maintenance of synapses in the brainstem, and assessed a potential dysfunction of the most vital central neuronal network in APLP1/APLP2-DKO mice by analyzing the respiratory network of the medulla. We performed in vivo unrestrained whole body plethysmography in newborn APLP1/APLP2-DKO mice at postnatal day zero. Additionally, we directly tested the activity of the respiratory network in an acute slice preparation that includes the pre-Bötzinger complex. In both sets of experiments, no significant differences were detected regarding respiratory rate and cycle variability, strongly arguing against central respiratory problems as the primary cause of death of APLP1/APLP2-DKO mice. Thus, we conclude that APLP1 and APLP2 are dispensable for the development of the network and the generation of a normal breathing rhythm.

Is It the Twilight of BACE1 Inhibitors?

“…Knockout mice lacking both APLP1 and APLP2 show postnatal lethality and growth deficiency, metabolic stress such as hypoglycemia, and central respiratory problems. On the other hand, their specific role within the CNS and PNS is still poorly understood [ 94 - 96 ].…”

Lack of APLP1 leads to subtle alterations in neuronal morphology but does not affect learning and memory

“…Gene knockout studies yielded important insights into physiological functions of the APP family for a variety of processes, notably synapse formation, maintenance and plasticity in vivo . While mouse mutants lacking only a single family member are fully viable, combined germline APP/APLP2 double knockout (DKO), APLP1/APLP2-DKO and APP/APLP1/APLP2 triple knockout (TKO) mice die shortly after birth ( Li et al, 1996 ; von Koch et al, 1997 ; Steinbach et al, 1998 ; Heber et al, 2000 ; Herms et al, 2004 ) due to impairments at the neuromuscular junction ( Wang et al, 2005 , 2009 ; Weyer et al, 2011 ; Klevanski et al, 2014 ; Han et al, 2017 ) revealing genetic evidence for partially overlapping functions. This is further corroborated by studies of conditional, brain-specific combined mutants ( Hick et al, 2015 ; Richter et al, 2018 ; Mehr et al, 2020 ; Steubler et al, 2021 ).…”

The Fate of Nascent APP in Hippocampal Neurons: A Live Cell Imaging Study

“…Amyloid precursor protein (APP) is well-known for its association with Alzheimer’s disease (AD), an incurable from of neurodegeneration prevalent in the elderly. In addition to its pathological connection, APP has been implicated in the development of neurons, , the maturation of synapses, the regulation of synaptic plasticity, and even the metabolism of cholesterol in the central nervous system (CNS). − APP’s various proteolytic pathways and different cleavage products underlie its diverse functions. One of the proteolysis pathways generates Aβ peptides, the major constituent of the amyloid plaques commonly found in AD patients’ brains.…”