Kunz L, Schröder TN, Lee H, Montag C, Lachmann B, Sariyska R, Reuter M, Stirnberg R, Stöcker T, Messing-Floeter PC, Fell J, Doeller CF, Axmacher N. Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease. Science. 2015 Oct 23;350(6259):430-3. PubMed.
Recommends
Please login to recommend the paper.
Comments
Arizona Alzheimer's Consortium
Kunz and colleagues report that entorhinal grid-cell function in young adult APOE e4 carriers is deficient relative to non-carriers. To put this in perspective, some background may be helpful. The close correlation between neuronal activity and spatial navigation in behaving rats led to the identification of place cells that, when sought in humans (with intracortical electrodes in neurosurgical patients), led to the distinction between hippocampal neurons sensitive to spatial location and parahippocampal neurons sensitive to specific landmarks (Ekstrom et al., 2003). Grid cells, in turn, are entorhinal neurons whose activity connects with hippocampal neurons with “place” characteristics (Jacobs et al., 2013). The hippocampus receives spatial and non-spatial input from the entorhinal cortex adding a precise spatiotemporal context to an experience (Knierim, 2015). In a carefully planned series of fMRI studies, Kunz et al. identified that young adult APOE e3/4 heterozygotes have deficient grid-cell-like responses relative to their e3/3 age mates. The age range of participants was 18 to 30 years, and performance on actual spatial memory tasks—although correlated with grid-cell responses—was unimpaired in the e4 carriers. The authors went on to demonstrate that increased hippocampal activity compensated for this grid-cell weakness. Previous studies comparing BOLD signal from APOE e4 carriers and non-carriers have been inconsistent with regard to whether medial temporal activation is enhanced or diminished in e4 carriers (Trachtenberg et al., 2012). Even so, a potentially important implication of this work is that chronically enhanced hippocampal activity may predispose to neurodegeneration and thus represent a potential therapeutic target for prevention.
This finding raises several clinically important questions:
1. Is deficient spatial navigation or spatial memory an early manifestation of AD?
Yes, but … bilateral hippocampal ablation, whether surgical or degenerative, results in a global amnestic syndrome that is clinically disabling, but seemingly no more so for spatial navigation than word-list learning. Spatial-memory impairment is not a unique early feature of AD, though it is certainly affected. However, this more likely represents a memory disorder than a spatial disorder. In contrast, visual variant AD is associated with asymmetric and highly disproportionate atrophy of posterior-visual-association cortices, not simply medial-temporal-lobe atrophy, and it produces severe visuospatial problems (simultanagnosia). Another visual syndrome in some patients with dementia, progressive prosopagnosia, results from frontotemporal lobar degeneration associated with TDP-43 inclusions. While this may impair the recognition of familiar landmarks, it does not produce the type of spatial navigational problems that typify patients with visual variant AD.
2. Since this deficiency was observed in young APOE e4 carriers, are e4 carriers handicapped?
While some studies have purported to show a difference, our own data have failed to demonstrate that e4 carriers have any handicap in educational, occupational, or financial attainment as young and working adults (Caselli et al., 2002). Whether this might reflect the compensation the authors demonstrate is unclear but certainly seems possible.
3. Is this neuronal overactivity causing neurodegeneration?
Excitotoxicity is an established mode of neuronal injury, but greater activity per se does not necessarily lead to neurodegeneration. The most bioenergetically active brain region, the striate cortex, is also the least vulnerable and least affected by AD. On the other hand, in a related study, Reiman and colleagues found greater right hippocampal activation on an fMRI task in presymptomatic PSEN1 carriers destined for neurodegeneration than non-carriers (Reiman et al., 2012). Assuming the grid-cell finding is developmental, it is difficult to know whether the accentuated hippocampal activity should be regarded as pathological or physiological. The vulnerability to future degeneration is clear, so it seems reasonable to ask whether this might be a potential target for preventive therapy.
4. Is this grid-cell deficiency an early sign of AD?
A number of studies have identified alterations in young adults that have been correlated with either subsequent AD (Snowdon et al., 1996) or APOE e4 carrier status (Reiman et al., 2004; Bartzokis et al., 2006; Valla et al., 2010), and APOE-related differences have even been identified in infants (Dean et al., 2014). Given how early such findings appear, it seems they are more likely developmental than degenerative in origin, although it may well be that developmental differences predispose to degenerative changes at older ages.
References:
Ekstrom AD, Kahana MJ, Caplan JB, Fields TA, Isham EA, Newman EL, Fried I. Cellular networks underlying human spatial navigation. Nature. 2003 Sep 11;425(6954):184-8. PubMed.
Jacobs J, Weidemann CT, Miller JF, Solway A, Burke JF, Wei XX, Suthana N, Sperling MR, Sharan AD, Fried I, Kahana MJ. Direct recordings of grid-like neuronal activity in human spatial navigation. Nat Neurosci. 2013 Sep;16(9):1188-90. Epub 2013 Aug 4 PubMed.
Knierim JJ. From the GPS to HM: Place cells, grid cells, and memory. Hippocampus. 2015 Jun;25(6):719-25. Epub 2015 Apr 15 PubMed.
Trachtenberg AJ, Filippini N, Mackay CE. The effects of APOE-ε4 on the BOLD response. Neurobiol Aging. 2012 Feb;33(2):323-34. PubMed.
Caselli RJ, Hentz JG, Osborne D, Graff-Radford NR, Barbieri CJ, Alexander GE, Hall GR, Reiman EM, Hardy J, Saunders AM. Apolipoprotein E and intellectual achievement. J Am Geriatr Soc. 2002 Jan;50(1):49-54. PubMed.
Reiman EM, Quiroz YT, Fleisher AS, Chen K, Velez-Pardo C, Jimenez-Del-Rio M, Fagan AM, Shah AR, Alvarez S, Arbelaez A, Giraldo M, Acosta-Baena N, Sperling RA, Dickerson B, Stern CE, Tirado V, Munoz C, Reiman RA, Huentelman MJ, Alexander GE, Langbaum JB, Kosik KS, Tariot PN, Lopera F. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012 Dec;11(12):1048-56. PubMed.
Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA. 1996 Feb 21;275(7):528-32. PubMed.
Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9. PubMed.
Bartzokis G, Lu PH, Geschwind DH, Edwards N, Mintz J, Cummings JL. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch Gen Psychiatry. 2006 Jan;63(1):63-72. PubMed.
Valla J, Yaari R, Wolf AB, Kusne Y, Beach TG, Roher AE, Corneveaux JJ, Huentelman MJ, Caselli RJ, Reiman EM. Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene. J Alzheimers Dis. 2010;22(1):307-13. PubMed.
Dean DC 3rd, Jerskey BA, Chen K, Protas H, Thiyyagura P, Roontiva A, O'Muircheartaigh J, Dirks H, Waskiewicz N, Lehman K, Siniard AL, Turk MN, Hua X, Madsen SK, Thompson PM, Fleisher AS, Huentelman MJ, Deoni SC, Reiman EM. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 2014 Jan;71(1):11-22. PubMed.
View all comments by Eric M. ReimanUniversity of Colorado School of Medicine
This study is an excellent example of basic neuroscience being extended to clinical relevance, and it presents a number of intriguing questions nicely detailed by Drs. Caselli and Reiman above. I would like to point out two additional areas of relevant research.
First, with regard to neuronal overactivity and its relationship to AD pathophysiology, there was an excellent study by Yamamoto et al. using optogenetic tools in APP transgenic mice to chronically increase firing in lateral entorhinal cortex neurons projecting to the dentate gyrus. This overactivation strongly increased amyloid deposition in the dentate gyrus. Hence, it is quite reasonable, as might be expected based on the link between amyloid production and synaptic activity (even under normal physiological conditions), that hippocampal circuit overactivity is linked to increased amyloid burden, and by extension, to AD vulnerability.
Additionally, let's consider APOE4. Given that APOE4 has been linked to modifications in both synaptic development (Dumanis et al., 2009) and signaling pathways underlying synaptic plasticity (Kim et al., 2014; Segev et al., 2015; Zhu et al., 2015), it is certainly plausible that multiple ways exist by which APOE is acting (even independently of its role in amyloid aggregation) to impact activity in these hippocampal circuits throughout the lifespan. Therefore, this finding provides support for studying the pleiotropic effects of APOE on brain function, and how these effects may relate to AD vulnerability.
The second study I wanted to comment on was previous work (covered by AlzForum) on place cells in AD. In that study, John O’Keefe (co-awardee of the 2014 Nobel Prize with May-Britt and Edvard Moser) and colleagues demonstrated that place cells activity could be assayed in vivo in AD mouse models (Cacucci et al., 2008), raising the possibility that similar methods could be employed to further examine these proposed grid cell effects using either an AD mouse model or an APOE4 mouse model (e.g., targeted replacement mice).
References:
Cacucci F, Yi M, Wills TJ, Chapman P, O'Keefe J. Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7863-8. PubMed.
Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, Ladu MJ, Weeber EJ, Turner RS, Xu B, Rebeck GW, Hoe HS. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci. 2009 Dec 2;29(48):15317-22. PubMed.
Kim J, Yoon H, Basak J, Kim J. Apolipoprotein E in synaptic plasticity and Alzheimer's disease: potential cellular and molecular mechanisms. Mol Cells. 2014 Nov;37(11):767-76. Epub 2014 Oct 30 PubMed.
Segev Y, Barrera I, Ounallah-Saad H, Wibrand K, Sporild I, Livne A, Rosenberg T, David O, Mints M, Bramham CR, Rosenblum K. PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice. J Neurosci. 2015 Sep 23;35(38):12986-93. PubMed.
Yamamoto K, Tanei Z, Hashimoto T, Wakabayashi T, Okuno H, Naka Y, Yizhar O, Fenno LE, Fukayama M, Bito H, Cirrito JR, Holtzman DM, Deisseroth K, Iwatsubo T. Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease. Cell Rep. 2015 May 12;11(6):859-65. Epub 2015 Apr 30 PubMed.
Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, Cardozo C, Haroutunian V, Robakis NK, Cai D. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11965-70. Epub 2015 Sep 8 PubMed.
View all comments by Andrew WolfMake a Comment
To make a comment you must login or register.