The normal role of AβPP and Aβ in the brain has been one of the most puzzling problems for the Alzheimer’s field, and even after years of effort, this problem remains unsolved. In today’s Neuron, Kamenetz et al. provide evidence for the role of Aβ in regulating neuronal excitability, which may shed light both on Aβ’s normal role in neuronal function and its role in AD pathogenesis.
Roberto Malinow’s group have been pioneers in the field of synaptic transmission and plasticity, and have used their elegant electrophysiological techniques to address the effects of acute AβPP expression on synaptic physiology. Through the use of organotypic hippocampal slice cultures and the sindbis virus expression method, the authors were able to endogenously overexpress AβPP, mutant AβPP and various AβPP derivatives. The authors were also able to evaluate the effects of neuronal activity on Aβ levels; they found that Aβ levels rose with increasing activity and fell with decreasing activity, and, furthermore, that this regulation occurred at the level of BACE cleavage. Overexpression of AβPP led to acute depression of synaptic transmission both in AMPA- and NMDA-mediated synaptic currents. This effect was blocked by γ-secretase inhibition and was mimicked by overexpression of the β-C-terminal fragment of AβPP (the product of BACE cleavage), thus implying that Aβ was mediating the depression in transmission. Suppression of neuronal activity blocked Aβ-mediated synaptic depression and, furthermore, required NMDA receptor activation, as NMDA blockade (which doesn’t affect overall neuronal excitability) also blocked Aβ-mediated depression.
Synaptic transmission was recorded from postsynaptic neurons that overexpressed AβPP, but could AβPP overexpression affect neighboring uninfected cells? The authors addressed this question by recording from neurons that were not themselves infected with AβPP, but were surrounded by cells that were, and then comparing the response with that of an uninfected neuron surrounded by other uninfected neurons. The results from this experiment showed that secreted Aβ could also depress transmission.
Finally, the authors showed that Aβ can act as a negative feedback regulator of neuronal activity. A pairing protocol was used to induce LTP in slices of transgenic mice overexpressing the Swedish mutation of APP. LTP was impaired as compared with wild-type mice, and this effect was blocked by a γ-secretase inhibitor. Although it would have been good to replicate this finding using acute expression of AβPP, the authors contend that the sudden increase in activity leads to an increase in Aβ and a decrease in transmission which offsets LTP. Repeated LTP-inducing stimuli in wild-type animals in the presence of a γ-secretase inhibitor did result in significantly larger potentiation, and thus the authors conclude that Aβ-induced depression can be recruited in normal animals.
The findings from this study have several implications for AD. One of the best correlates for the severity of cognitive deficits in AD is synaptic loss (Scheff et al., 1990; Terry et al., 1991). In fact, based on computer models of neuronal networks, it has been suggested that the loss of synapses can explain all the cognitive symptoms of AD, and that the initial stages of dementia can even occur from synaptic dysfunction that precedes synaptic loss (Horn et al., 1996). All the AβPP overexpressing transgenic mice so far studied exhibit impairments in synaptic functioning. LTP impairments, without deficits in basal transmission, have been observed in four- to five-month-old (Larson et al., 1999) and five- to seven-month-old mice (Moechars et al., 1999), both prior to plaque deposition and 16-month-old mice with plaques (Chapman et al., 1999). Others find impaired synaptic transmission but no change in LTP in two- to four-month-old mice, prior to plaque deposition (Hsia et al., 1999) and 12- to 18-month-old mice with plaques (Fitzjohn et al., 2001). Basal transmission and LTP deficits have also been observed in mice that develop both plaque and tau pathology, and were evident at an age prior to plaque and tangle formation (Shepherd et al., 2002). It is conceivable that impairments in plasticity processes such as LTP, which are thought to underlie at least some forms of learning and memory, could result in the initial cognitive dysfunction in AD. If so, treatments that only affect plaque deposition in the late stages of AD may not alleviate all the symptoms of the disease. Severe synaptic depression of activity via Aβ may also result in loss of synapses in a use-it-or-lose-it manner. This study also opens up the intriguing possibility that changes in neuronal activity in the aging brain, perhaps brought on by environmental or genetic triggers, may cause disruption of Aβ’s feedback system, ultimately resulting in full-blown AD.
This paper opens up a new avenue of exploration in AD and possible therapeutic targets. What is the mechanism by which Aβ affects synaptic transmission? How does synaptic activity affect BACE cleavage? Why do BACE and AβPP knockout mice show no severe neuronal phenotype? What is the role of NMDA receptors in the signaling pathway induced by Aβ? These are just some of the intriguing questions that now remain to be explored. This paper shows the benefits of utilizing techniques and knowledge gained from studies in normal synaptic functioning to investigate a neurologic disease. Hopefully this is just the start of a synthesis of basic neuroscience and disease research.
References:
Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 1999 Mar;2(3):271-6.
Abstract
Fitzjohn SM, Morton RA, Kuenzi F, Rosahl TW, Shearman M, Lewis H, Smith D, Reynolds DS, Davies CH, Collingridge GL, Seabrook GR. Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein. J Neurosci 2001 Jul 1;21(13):4691-8.
Abstract
Horn D, Levy N, Ruppin E. Neuronal-based synaptic compensation: a computational study in Alzheimer's disease. Neural Comput 1996 Aug 15;8(6):1227-43.
Abstract
Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3228-33.
Abstract
Larson J, Lynch G, Games D, Seubert P. Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. Brain Res. 1999 Sep 4;840(1-2):23-35.
Abstract
Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999 Mar 5;274(10):6483-92.
Abstract
Scheff SW, Price DA, Sparks DL. Quantitative assessment of cortical synaptic density in Alzheimer's disease. Neurobiol Aging. 2001 May-Jun;22(3):355-65.
Abstract
Shepherd JD, Oddo S, LaFerla FM (2002) Synaptic dysfunction in triple transgenic model of Alzheimer's disease. In: The 3rd Neurobiology of Aging Conference. Orlando, USA.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572-80.
Abstract
View all comments by Jason Shepherd
Home
I recommend the Primary Papers
