Selective neurotoxicity of COOH-terminal fragments of the β-amyloid precursor protein

doi:10.1016/0304-3940(93)90192-N

Neuroscience Letters

Volume 154, Issues 1–2, 14 May 1993, Pages 145-148

https://doi.org/10.1016/0304-3940(93)90192-N Get rights and content

Abstract

The primary component of amyloid deposits found in the brains of patients with Alzheimer's disease is the β-amyloid protein, a derivative of a much larger precursor protein (βPP). We have previously reported that overexpression of carboxyl (COOH)-terminal fragments of βPP from an integrated DNA construct leads to degeneration of neuronally differentiating mouse embryonic stem cells and that the neuronal degeneration is related to approximately 14- and 15-kDa COOH-terminal fragments of the precursor protein. We here demonstrate that these putative cytotoxic fragments contain intact β-amyloid protein. When such transformed cell lines are treated with dimethyl sulfoxide to induce differentiation into muscle cells, however, the resulting muscle cells remain viable (as do control non-transformed cells), despite the production of comparable amounts of the 14- and 15-kDa fragments. These results are consistent with the hypothesis that particular COOH-terminal fragments of βPP are amyloidogenic and neurotoxic.

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Citation Excerpt :
In addition, two separate mouse lines expressing APP751WT regulated by the rat neuron-specific Nse promoter are available (Mucke et al., 1994; Quon et al., 1991), together with APP WT regulated by the PDGFβ promoter (line I5) (Mucke et al., 2000). In view of the neurotoxic properties of C-terminal fragments in cell cultures (Fukuchi et al., 1993; Kim and Suh, 1996) and their accumulation in Alzheimer brain (McPhie et al., 1997), liable to influence disease onset and progression (Turner et al., 2003), it is of interest to examine their neurobehavioural impact. APP/C104 mice with the human 104-amino acid C-terminal fragment transgene driven by the human NEFL promoter have Aβ plaques surrounded by reactive microglia and astrocytes as well as reduced neuronal counts in the CA1 hippocampal subregion (Nalbantoglu et al., 1997).
The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioural and psychological symptoms of Alzheimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine.
Neuronal neprilysin overexpression is associated with attenuation of Aβ-related spatial memory deficit
2006, Neurobiology of Disease
Converging evidence links abnormally high brain concentrations of amyloid-β peptides (Aβ) to the pathology of Alzheimer's disease (AD). Lowering brain Aβ levels, therefore, is a therapeutic strategy for the treatment of AD. Neuronal neprilysin upregulation led to increased degradation of Aβ, reduced the formation of Aβ-plaques and the associated cytopathology, but whether overexpression of neprilysin can improve cognition is unknown. We show that neuronal overexpression of neprilysin improved the Morris water maze memory performance in mice with memory deficits resulting from overexpression of the AD-causing mutated human amyloid precursor protein (APP). This improvement was associated with decreased brain levels of Aβ and with unchanged endoproteolytic processing of APP. These results provide the evidence that lowering of brain Aβ levels by increasing its degradation can improve cognitive functions in vivo, and suggest that increasing the activity of neprilysin in brain may be effective in preventing cognitive decline in AD.
Transgenic mice expressing the human C99 terminal fragment of βAPP: Effects on cytochrome oxidase activity in skeletal muscle and brain
2004, Journal of Chemical Neuroanatomy
In order to furnish a combined model of relevance to human inclusion-body myopathy and Alzheimer’s disease, transgenic mice expressing human βAPP-C99 in skeletal muscle and brain under the control of the cytomegalovirus/β-actin promoter were produced (Tg13592). These transgenic mice develop Aβ deposits in muscles but not in brain. Cell metabolic activity was analyzed in brain regions and muscle by cytochrome oxidase (CO) histochemistry, the terminal enzyme of the electron transport chain. By comparison to age-matched controls of the C57BL/6 strain, CO activity was selectively increased in dark skeletal muscle fibers of Tg13592 mice. In addition, only increases in CO activity were obtained in those brain regions where a significant difference appeared. The CO activity of Tg13592 mice was elevated in several thalamic nuclei, including laterodorsal, ventromedial, and midline as well as submedial, intralaminar, and reticular. In contrast, the groups did not differ in most cortical regions, except for prefrontal, secondary motor, and auditory cortices, and in most brainstem regions, except for cerebellar (fastigial and interpositus) nuclei and related areas (red and lateral vestibular nuclei). No variation in cell density and surface area appeared in conjunction with these enzymatic alterations. The overproduction of βAPP-C99 fragments in brain without (amyloidosis did not appear to affect the metabolic activity of structures particularly vulnerable in Alzheimer’s disease.
No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the β-cleaved C-terminal APP fragment
2003, Neurobiology of Disease
Previous studies in the literature have resulted in conflicting reports on the potential neurotoxicity of the β-cleaved Alzheimer’s disease C-terminal fragment (β-CTF) of β-amyloid precursor protein in vivo. To readdress this question by rigorous quantitative methods, we analyzed transgenic mice expressing human β-CTF with the I45F mutation (SPA4CT) under control of the prion protein promoter by stereological techniques. The transgene was expressed in hippocampus and cortex in large pyramidal neurons and in dentate gyrus granule cells. Proteolytic processing of β-CTF released Aβ. However, most of it remained uncleaved. Neurodegeneration was evaluated by investigating the numbers of hippocampal pyramidal and granule neurons, as well as the number of synaptophysin-immunopositive presynaptic boutons in the hippocampus of 15-month-old SPA4CT mice with design-based stereological techniques. The analyses showed that a fourfold higher expression of the transgene compared to murine APP levels had no effect on the numbers of both neurons and synaptophysin-immunopositive presynaptic boutons. These data implicate that expression of β-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer’s disease brain.
Transgenic mice expressing the human C99 terminal fragment of βAPP: Effects on spatial learning, exploration, anxiety, and motor coordination
2002, Experimental Gerontology
The functional consequence of beta-amyloid precursor protein (βAPP) manipulation on behavior was assessed in Tg13592 mice, characterized by transgene expression of the 99 amino acid C-terminal sequence of human βAPP in brain and skeletal muscle but with plaque formation only in muscle. By comparison to the C57BL/6 background strain controlled for age and gender, Tg13592 transgenic mice had fewer movements in an automated chamber and fewer enclosed arm entries in the elevated plus-maze. This hypoactivity was probably due to a loss in the motivation to explore novel environmental stimuli rather than motor weakness or anxiety. In addition, the acquisition of place learning in the Morris water maze task was impaired in Tg13592 mice. The transgenic mice were not impaired in a probe trial or while swimming toward a visible platform. These results are concordant with the hypothesis that transgene expression of the C-terminal sequence of human βAPP in brain is sufficient for causing behavioral abnormalities. The hypoactivity and the spatial learning deficit were associated with higher cytochrome oxidase activity seen in thalamic nuclei, indicating that altered regional brain metabolism caused by βAPP transgene expression may be responsible for the behavioral changes.
Alzheimer's disease: A dysfunction of the amyloid precursor protein
2000, Brain Research
Citation Excerpt :
Interestingly, we had proposed previously that C100 is involved in the etiology of Alzheimer disease [73]. It is neurotoxic in vitro [116,24,97,101,57] and is amyloidogenic [17–19,64,111,27,105]. In addition, expression of C100 in vivo can cause neuropathology that is similar in some ways to that in AD, including neurodegeneration and cognitive dysfunction [3,25,48,71,72,80,91,104], as well as increases in acetylcholinesterase [92] and abnormalities in synaptic transmission [28].
In this review, we argue that at least one insult that causes Alzheimer’s disease (AD) is disruption of the normal function of the amyloid precursor protein (APP). Familial Alzheimer’s disease (FAD) mutations in APP cause a disease phenotype that is identical (with the exception that they cause an earlier onset of the disease) to that of ‘sporadic’ AD. This suggests that there are molecular pathways common to FAD and sporadic AD. In addition, all individuals with Down syndrome, who carry an extra copy of chromosome 21 and overexpress APP several-fold in the brain, develop the pathology of AD if they live past the age of 40. These data support the primacy of APP in the disease. Although APP is the source of the β-amyloid (Aβ) that is deposited in amyloid plaques in AD brain, the primacy of APP in AD may not lie in the production of Aβ from this molecule. We suggest instead that APP normally functions in the brain as a cell surface signaling molecule, and that a disruption of this normal function of APP is at least one cause of the neurodegeneration and consequent dementia in AD. We hypothesize in addition that disruption of the normal signaling function of APP causes cell cycle abnormalities in the neuron, and that these abnormalities constitute one mechanism of neuronal death in AD. Data supporting these hypotheses have come from investigations of the molecular consequences of neuronal expression of FAD mutants of APP or overexpression of wild type APP, as well as from identification of binding proteins for the carboxyl-terminus (C-terminus) of APP.

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Selective neurotoxicity of COOH-terminal fragments of the β-amyloid precursor protein

Abstract

Biochem. Biophys. Res. Commun.

Mol. Brain Res.

Neurosci. Lett.

Cleavage of amyloid β peptide during constitutive processing of its precursor

Science

Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor

Science

Increased expression of β-amyloid protein precursor and microtubuleassociated protein tau during the differentiation of murine embryonal carcinoma cells

J. Neurochem.

Processing of the amyloid protein precursor to potentially amyloidogenic derivatives

Science

Framing β-amyloid

Nature Genet.