This paper is very interesting. The authors show decreased synaptic AMPARs leading to disrupted plasticity and episodic-like memory in a double knock-in model of AD. This work, in the context of other studies in vitro and in vivo showing amyloid-related synaptic changes including NMDAR internalization and dendritic spine loss and changes in plasticity, strongly suggests that amyloid-associated synaptotoxicity contributes to cognitive decline in AD.

View all comments by Tara Spires

This study is very interesting. The authors explore how cognitive deficits arise in Alzheimer disease using a knock-in mouse model where, without overexpression of transgenes, there is accumulation of β amyloid with aging. The authors perform extensive electrophysiological characterization of these mice at three different stages, pre-plaque (young), few plaques (middle-age) and robust deposition (old). While normal at young age, basal synaptic transmission and long-term plasticity was impaired after middle age, before major plaque load.

Mechanistically, the authors find by quantitative immuno-EM that although there was no reduction in the number of AMPA-containing spines, there was a small reduction in the amount of AMPA gold particles in old 2xKI mice. I was a bit surprised by this small difference given that the differences in AMPA currents were dramatic. I suspect that this is due to EM not being an optimal method for quantitative analysis.

In summary, the authors provide convincing data confirming that changes in AMPA receptors may be an early feature of Aβ-induced...  Read more

This study is very interesting. The authors explore how cognitive deficits arise in Alzheimer disease using a knock-in mouse model where, without overexpression of transgenes, there is accumulation of β amyloid with aging. The authors perform extensive electrophysiological characterization of these mice at three different stages, pre-plaque (young), few plaques (middle-age) and robust deposition (old). While normal at young age, basal synaptic transmission and long-term plasticity was impaired after middle age, before major plaque load.

Mechanistically, the authors find by quantitative immuno-EM that although there was no reduction in the number of AMPA-containing spines, there was a small reduction in the amount of AMPA gold particles in old 2xKI mice. I was a bit surprised by this small difference given that the differences in AMPA currents were dramatic. I suspect that this is due to EM not being an optimal method for quantitative analysis.

In summary, the authors provide convincing data confirming that changes in AMPA receptors may be an early feature of Aβ-induced synaptic dysfunction. In the discussion, the authors suggest that their results are discrepant from those of Kamenetz et al. (2003) and Snyder et al. (2005) because these studies found NMDA receptor changes. Chang et al. suggest that this discrepancy may be because these two studies addressed “acute” alterations, that is, minutes to hours after either addition of Aβ or transfection with APP constructs. However, in Snyder et al. we did, in fact, observe surface NMDA receptor (NR1) reductions in neurons of Tg2576 mice that progressively accumulate Aβ42 over days in culture (see Takahashi, 2004).

The authors may also want to read our published work on early reductions in GluR1 AMPA receptor subunits in cultured neurons derived from APP mutant Tg2576 mice (Almeida et al., 2005). In this study we found that, early on, spine density was reduced and, later on, that is, in older cultures, the alterations were more pronounced and also included presynaptic changes. These correlate with increased accumulation and oligomerization of Aβ42 in these neurons. We also observed that alterations in synaptic AMPA receptors were more pronounced than those of NMDA receptors in Tg2576 neurons. Our data support this present study by Chang et al., since it suggests that it is possible that AMPA receptors are affected earlier, and NMDA receptors later, due to the progressive accumulation of Aβ. Therefore I disagree with the authors’ affirmation that one cannot make conclusions from cultured neurons. Neurons in culture are a limited model but so are mouse models; together they all may help us to better understand AD pathogenesis.

View all comments by Claudia Almeida

I think it would be worthwhile to look at the brain of older people who have used marijuana chronically and compare it with the brain of age-matched people who never used it. This simple comparison could throw added light on whether cannabis could help people with Alzheimer disease.

View all comments by Olorunyomi Olowosegun

The research is very interesting and important. In Los Angeles, California, use of medical cannabis is encountered working in the field with adolescents or young adults. There is indeed controversy since hidden side effects include perceptual and family disorders. Those also need consideration at the psychosocial level.

At the neuronal level, cannabinoid research also needs to rule out an effect of cannabinoids on reducing prion fibrils (see Colin et al., 1999) or neurogenesis (La Spada, 2005). Neuroendocrine effects, prolactin release, gonadal atrophy, and tumor genesis need attention when studying cannabinoids.

References:
Combs CK, Johnson DE, Cannady SB, Lehman TM, Landreth GE. Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. J Neurosci. 1999 Feb 1;19(3):928-39. Abstract

La Spada AR. Huntington's disease and neurogenesis: FGF-2 to the rescue? Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17889-90. Epub 2005 Dec 5. No abstract available. Abstract

View all comments by Kiumars Lalezarzadeh

Cannabinoid agonist is shown to have a thermal hyperalgesia effect in inflammatory pain involving the sensory pathways and activation of the calcineurin (Nathaniel et al., 2006). The role of sensory inhibition, anhedonia, and known effects of calcineurin in psychosis also need consideration.

References:
Nathaniel A. Jeske, Amol M. Patwardhan, Nikita Gamper, Theodore J. Price, Armen N. Akopian, and Kenneth M. Hargreaves (2006, September 5). Cannabinoid WIN 55,212-2 regulates TRPV1 phosphorylation in sensory neurons. J. Biol. Chem, 10.1074/jbc.M603220200

View all comments by Kiumars Lalezarzadeh