Normal function of A beta? Relation of A beta to brain activity?

View all comments by Paul Coleman

This paper confirms recent studies that demonstrate a decrease in AMPA receptor activity as a consequence of exposure to Aβ peptides, but it is more than just confirmatory. The earlier studies employed exogenous Aβ at relatively high concentrations, experiments that are always open to question. This new work suggests that endogenous Aβ is the likely agent responsible for the decrease in synaptic transmission. Their use of a mutant APP incapable of generating Aβ is a new approach that has great potential for further studies.

View all comments by Vincent Marchesi

Ting et al. provide an interesting and well-done analysis of how endogenous Abeta may depress synaptic transmission, namely by depressing AMPA receptor-mediated EPSCs. Also, the authors find subtle presynaptic deficits in synaptic vesicle cycling with unknown consequences for synaptic communication. The key here is the possibility that cellularly derived Abeta may be causing these effects, thereby bypassing problems related to Abeta concentration or Abeta conformation typically associated with exogenously applied Abeta. It will eventually be useful to know the specific types of Abeta that are responsible for this phenomenon.

Several groups have demonstrated that synaptic activity can regulate release of Abeta from neurons (Kamenetz et al., 2003, Cirrito et al., 2005 ). Is activity-dependent release of Abeta necessary for this phenomenon, or is Abeta release via other mechanisms sufficient to mediate the effect on AMPA receptors? These questions ultimately address whether Abeta may act...  Read more

Ting et al. provide an interesting and well-done analysis of how endogenous Abeta may depress synaptic transmission, namely by depressing AMPA receptor-mediated EPSCs. Also, the authors find subtle presynaptic deficits in synaptic vesicle cycling with unknown consequences for synaptic communication. The key here is the possibility that cellularly derived Abeta may be causing these effects, thereby bypassing problems related to Abeta concentration or Abeta conformation typically associated with exogenously applied Abeta. It will eventually be useful to know the specific types of Abeta that are responsible for this phenomenon.

Several groups have demonstrated that synaptic activity can regulate release of Abeta from neurons (Kamenetz et al., 2003, Cirrito et al., 2005 ). Is activity-dependent release of Abeta necessary for this phenomenon, or is Abeta release via other mechanisms sufficient to mediate the effect on AMPA receptors? These questions ultimately address whether Abeta may act as a negative feedback signal for synaptic transmission.

APP with a mutation at the BACE cleavage site was a very clever tool to use in these studies. As the authors note, while this vector suggests that Abeta could be a key mediator of the effects seen here, other APP cleavage products are also affected and therefore cannot be excluded.

View all comments by John Cirrito

Our PNAS study identifies deficits in synaptic transmission when APP is overexpressed in neurons. We use Semliki Forest virus to rapidly upregulate APP in autaptic (isolated microisland) cultures of hippocampal neurons, and record synaptic responses 12 to 24 hours after infection. Our finding that AMPA receptor-mediated responses are reduced in neurons overexpressing APP is consistent with a number of recent studies reporting APP- or Aβ-mediated internalization of AMPA receptors (e.g., Almeida et al., 2005; Roselli et al., 2005; Hsieh et al., 2006).

One notable difference between our study and that of Hsieh et al. is that we do not observe a decrease in NMDA receptor-mediated synaptic responses. I believe we fortuitously caught our synapses at a point predicted but not seen by Hsieh et al.—that is, after AMPA receptor removal but prior to spine retraction—by recording a few hours earlier after infection than Hsieh et al. We also identified a presynaptic deficit in synaptic vesicle recycling that has implications for neurotransmission in response to extended trains of action...  Read more

Our PNAS study identifies deficits in synaptic transmission when APP is overexpressed in neurons. We use Semliki Forest virus to rapidly upregulate APP in autaptic (isolated microisland) cultures of hippocampal neurons, and record synaptic responses 12 to 24 hours after infection. Our finding that AMPA receptor-mediated responses are reduced in neurons overexpressing APP is consistent with a number of recent studies reporting APP- or Aβ-mediated internalization of AMPA receptors (e.g., Almeida et al., 2005; Roselli et al., 2005; Hsieh et al., 2006).

One notable difference between our study and that of Hsieh et al. is that we do not observe a decrease in NMDA receptor-mediated synaptic responses. I believe we fortuitously caught our synapses at a point predicted but not seen by Hsieh et al.—that is, after AMPA receptor removal but prior to spine retraction—by recording a few hours earlier after infection than Hsieh et al. We also identified a presynaptic deficit in synaptic vesicle recycling that has implications for neurotransmission in response to extended trains of action potentials.

References:
Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. Abstract

Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. Abstract

Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF. Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci. 2005 Nov 30;25(48):11061-70. Abstract

View all comments by Jane Sullivan

Amyloid-β Shows Another Facet
In this article, Brody et al. showed that concentrations of amyloid-β (Aβ) in brain interstitial fluid (ISF), in vivo, increased following head injury and subarachnoid hemorrhage as neurological status improved. Conversely, concentrations of Aβ fell when neurological status declined. The authors conclude that neuronal activity regulates the concentration of extracellular Aβ, and that declining levels of Aβ reflect depressed neuronal function.

To some extent, Brody et al. underestimate the potential significance of their findings. As emphasized by the authors, observations derived from in vivo studies in human patients are extremely valuable as they relate directly to the human condition and allow the generation of hypotheses that can be tested experimentally. In addition, their studies have produced data regarding the physiological functions of soluble Aβ that are relevant to the role of Aβ in Alzheimer disease (AD).

A number of recent studies suggest that soluble Aβ in the brain may have a more significant role in the pathogenesis...  Read more

Amyloid-β Shows Another Facet
In this article, Brody et al. showed that concentrations of amyloid-β (Aβ) in brain interstitial fluid (ISF), in vivo, increased following head injury and subarachnoid hemorrhage as neurological status improved. Conversely, concentrations of Aβ fell when neurological status declined. The authors conclude that neuronal activity regulates the concentration of extracellular Aβ, and that declining levels of Aβ reflect depressed neuronal function.

To some extent, Brody et al. underestimate the potential significance of their findings. As emphasized by the authors, observations derived from in vivo studies in human patients are extremely valuable as they relate directly to the human condition and allow the generation of hypotheses that can be tested experimentally. In addition, their studies have produced data regarding the physiological functions of soluble Aβ that are relevant to the role of Aβ in Alzheimer disease (AD).

A number of recent studies suggest that soluble Aβ in the brain may have a more significant role in the pathogenesis of AD than the plaques of insoluble Aβ. PET imaging has shown that, as a group, patients with mild cognitive impairment have a similar amount of insoluble Aβ in their brains as patients with AD [3]. Furthermore, removal of Aβ plaques from the brain does not prevent progressive neurodegeneration in AD [2]. Other studies indicate that high levels of soluble Aβ in the brain correlate more closely with cognitive decline in AD than does insoluble Aβ plaque load [5,6] and that removal of Aβ plaques from the brain by Aβ immunotherapy increases the level of soluble Aβ in the brain [8].

The perceived role of soluble Aβ in the pathogenesis of cognitive impairment in AD makes it all the more urgent to take a fresh look at the physiological and pathological roles of Aβ. Little is known about the physiological role of soluble Aβ in the brain in vivo. The result’s of Brody et al. suggest that neurons produce Aβ in response to acute brain injury and that the higher levels of Aβ in the subcortical white matter correlate with improvement of neurological status. But, why should the levels of soluble Aβ rise in those patients showing improvement in neurological status?

Levels of soluble Aβ in the brain depend not only on its level of production but also on the efficiency of elimination of Aβ from the interstitial fluid [11]. Several pathways for elimination of Aβ are recognized; they include degradation by neprilysin and absorption into the blood by various mechanisms [11]. Aβ also drains with brain ISF along basement membranes in the walls of cerebral capillaries and arteries where it may deposit as cerebral amyloid angiopathy (CAA) [11]. The rise in concentration of Aβ in the ISF during the recovery period following acute brain injury in the study of Brody et al. could reflect a reduction of elimination of Aβ as well as its increased production.

Failure of elimination of Aβ along perivascular drainage routes and the development of CAA is observed with increasing age when arteries stiffen [11] and following denervation [1] when vessel tone may be affected. Diffuse vascular injury is well recognized in patients with head injuries [9], and vascular spasm is seen in both head injury and following subarachnoid hemorrhage [7]. Vascular factors may play a role in impeding the elimination of Aβ along artery walls and in the development of CAA following head injury [4].

Brody et al. emphasize that their results correlate with in vitro studies showing that neuronal and synaptic activity dynamically regulates the concentration of extracellular soluble Aβ. However, it is not known whether the effects of the increased production of Aβ are purely local or whether Aβ has an effect on artery walls as it drains out of the brain along perivascular pathways.

The role of Aβ in the pathogenesis of AD requires some re-evaluation. Aβ in its soluble form in the brain seems to be as important as insoluble plaques of Aβ, if not more important, in the pathogenesis of AD. Toxic forms of soluble Aβ appear to have a role in the pathogenesis of AD [10], and the techniques used by Brody et al. may provide the opportunity to study this further in vivo. However, we may ask whether toxicity is the sole role for Aβ in AD. The deposition of fibrillar Aβ in the perivascular drainage pathways in CAA may block the elimination not only of Aβ but also of other brain metabolites. This may lead to loss of homeostasis and neuronal malfunction as a factor in cognitive impairment in AD. Evaluation of the composition of brain ISF may help to answer questions about the quality of the neuronal environment in patients with AD.

References:
1. Beach TG, Potter PE, Kuo YM, Emmerling MR, Durham RA, Webster SD, Walker DG, Sue LI, Scott S, Layne KJ, Roher AE (2000) Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci Lett 283:9-12. Abstract

2. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216-223. Abstract

3. Kemppainen NM, Aalto S, Wilson IA, Någren K, Helin S, Brück A, Oikonen V, Kailajärvi M, Scheinin M, Viitanen M, Parkkola R, Rinne JO (2007) PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment. Neurology 68:1603-1606. Abstract

4. Leclercq PD, Murray LS, Smith C, Graham DI, Nicoll JA, Gentleman SM (2005) Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype. J Neurol Neurosurg Psychiatry 76:229-233. Abstract

5. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155:853-862. Abstract

6. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 46:860-866. Abstract

7. Oertel M, Boscardin WJ, Obrist WD, Glenn TC, McArthur DL, Gravori T, Lee JH, Martin NA (2005) Posttraumatic vasospasm: the epidemiology, severity, and time course of an underestimated phenomenon: a prospective study performed in 299 patients. J Neurosurg 103:812-824. Abstract

8. Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle GD, Luehrs DC, Kuo YM, Lopez J, Brune D, Ferrer I, Masliah E, Newel AJ, Beach TG, Castano EM, Roher AE (2006) Amyloid-{beta} Peptide Remnants in AN-1792-Immunized Alzheimer's Disease Patients: A Biochemical Analysis. . Am J Pathol 169:1048-1063. Abstract

9. Pittella JE, Gusmão SN (2003) Diffuse vascular injury in fatal road traffic accident victims: its relationship to diffuse axonal injury. J Forensic Sci 48:626-630. Abstract

10. Walsh DM, Selkoe DJ (2007) Abeta Oligomers - a decade of discovery. J Neurochem 101:1172-1184. Abstract

11. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular Drainage of Amyloid-beta Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer's Disease. Brain Pathol 18:253-266. Abstract

View all comments by Roy O. Weller

The recent report by Kang et al. suggests not only that amyloid may serve an important role in sleep regulation, but also further highlights the need for additional studies on its physiological role. The study shows that amyloid is at least a biomarker of sleep, but it is interesting to note that it may also provide a mechanistic link mediating orexinergic signaling that pushes brain systems toward sleep. These findings are especially compelling considering other identified physiological effects of amyloid/APP, for example, Aβ feedback synaptic inhibition (Hsieh et al., 2006) or amyloid-enhanced potassium channel conductance (Furukawa et al., 1996). These physiological effects may be linked to slow wave sleep oscillations and neuronal quiescence (Vyazovskiy et al., 2009).

However, it is also important to note that there are likely to be multiple players in sleep regulation. For example, earlier work indicates BDNF and Homer1a also play...  Read more

The recent report by Kang et al. suggests not only that amyloid may serve an important role in sleep regulation, but also further highlights the need for additional studies on its physiological role. The study shows that amyloid is at least a biomarker of sleep, but it is interesting to note that it may also provide a mechanistic link mediating orexinergic signaling that pushes brain systems toward sleep. These findings are especially compelling considering other identified physiological effects of amyloid/APP, for example, Aβ feedback synaptic inhibition (Hsieh et al., 2006) or amyloid-enhanced potassium channel conductance (Furukawa et al., 1996). These physiological effects may be linked to slow wave sleep oscillations and neuronal quiescence (Vyazovskiy et al., 2009).

However, it is also important to note that there are likely to be multiple players in sleep regulation. For example, earlier work indicates BDNF and Homer1a also play roles (Faraguna et al., 2008; Mackiewicz et al., 2008), and it will be interesting to see what specific role amyloid may play in the molecular networks associated with sleep. Future studies combining multiple techniques (for instance, EEG, cognition, and microarray) may be particularly well suited for elucidating interactions among complex networks regulating sleep and the consequences of its disruption.

View all comments by Eric Blalock