It is becoming increasingly recognized that there is significant interneuron degeneration in Alzheimer's disease. As the hippocampus is integral for learning and memory, we performed a systematic review of primary literature focused on the relationship between Alzheimer's and hippocampal interneurons. In this study, we summarize the experimental work performed to date and identify opportunities for future experiments.
Objectives:
This PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-style systematic review seeks to summarize the findings of all accessible research focused on cholecystokinin (CCK), neuropeptide Y (NPY), parvalbumin (PV), and somatostatin (SOM) interneurons in the hippocampal formation.
Results:
One thousand five hundred ninety-three articles were pulled from PubMed, PsycInfo, and Web of Science, based on three blocks of search terms. There were 45 articles that met all the predetermined inclusion/exclusion criteria. There is strong evidence that PV interneurons are affected early in the disease by toxic amyloid beta (Aβ) fragments; SOM interneurons are affected indirectly while the SOM neuropeptide may act to slowly worsen toxic Aβ fragment accumulation, whereas NPY- and CCK-positive interneurons are affected later in the progression of the disease.
Conclusions:
Fewer studies have been performed on NPY and CCK interneurons, and there is room for further investigations regarding the role of PV interneurons in Alzheimer's to help resolve contradictory findings. This review found that PV interneurons are affected early in the disease, but only in Alzheimer's precursor protein but not tau models. NPY and CCK interneurons were found to be affected later in the disease, and SOM interneurons vary greatly. Future studies may consider reporting immunohistochemical studies inclusive of either cell location or morphology—as well as marker to give a more robust picture of the disease.
Impact statement
In the past decade, the contribution of hippocampal interneurons to the pathology of Alzheimer's disease has been increasingly recognized. The goal of this systematic review was to summarize findings to better determine the focus of the work to date, to help identify where there is consensus in the research, and to elucidate future avenues of inquiry.
Get full access to this article
View all access options for this article.
References
1.
AbbasAI, SundiangMJM, HenochB, et al.2018. Somatostatin interneurons facilitate hippocampal-prefrontal synchrony and prefrontal spatial Encoding. Neuron, 100:926–939.e3.
2.
Aguado-LleraD, CanellesS, FragoLM, et al.2018. The protective effects of IGF-I against β-amyloid-related downregulation of hippocampal somatostatinergic system involve activation of Akt and protein kinase A. Neuroscience, 374:104–118.
3.
AhnaouA, MoecharsD, RaeymaekersL, et al.2017. Emergence of early alterations in network oscillations and functional connectivity in a tau seeding mouse model of Alzheimer's disease pathology. Sci Rep, 7:14189.
4.
AlbuquerqueMS, MaharI, DavoliMA, et al.2015. Regional and sub-regional differences in hippocampal GABAergic neuronal vulnerability in the TgCRND8 mouse model of Alzheimer's disease. Front Aging Neurosci, 7:30.
5.
Arevalo-SerranoJ, Sanz-AnquelaJM, Gonzalo-RuizA. 2008. Beta-amyloid peptide-induced modifications in alpha 7 nicotinic acetylcholine receptor immunoreactivity in the hippocampus of the rat: relationship with GABAergic and calcium-binding proteins perikarya. Brain Res Bull, 75:533–544.
6.
AsoE, Andres-BenitoP, FerrerI. 2018. Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer like symptoms in a transgenic animal model. Biochem Pharmacol, 157:210–216.
7.
AsoE, Sánchez-PlaA, Vegas-LozanoE, et al.2015. Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. J Alzheimers Dis, 43:977–991.
8.
BallardC, GauthierS, CorbettA, et al.2011. Alzheimer's disease. Lancet, 377:1019–1031.
9.
BloomGS. 2014. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol, 71:505–508.
10.
BoehmS, BetzH. 1997. Somatostatin inhibits excitatory transmission at rat hippocampal synapses via presynaptic receptors. J Neurosci, 17:4066–4075.
11.
BranchSY, SharmaR, BecksteadMJ. 2014. Aging decreases L-type calcium channel currents and pacemaker firing fidelity in substantia nigra dopamine neurons. J Neurosci, 34:9310–9318.
12.
BrazeauP, ValeW, BurgusR, et al.1973. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science, 179:77–79.
13.
Brown University. 2019. Mixed results of cannabinoids for agitation in Alzheimer's disease. Psychopharmacol Update, 30:8.
14.
Burgos-RamosE, Hervas-AguilarA, Puebla-JiménezL, et al.2007. Chronic but not acute intracerebroventricular administration of amyloid beta-peptide(25–35) decreases somatostatin content, adenylate cyclase activity, somatostatin-induced inhibition of adenylate cyclase activity, and adenylate cyclase I levels in the RA. J Neurosci Res, 85:433–442.
15.
CaccavanoA, BozzelliPL, ForcelliPA, et al.2020. Inhibitory parvalbumin basket cell activity is selectively reduced during hippocampal sharp wave ripples in a mouse model of familial Alzheimer's disease. J Neurosci, 40:5116–5136.
16.
CammalleriM, BagnoliP, BigianiA. 2019. Molecular and cellular mechanisms underlying somatostatin-based signaling in two model neural networks, the retina and the hippocampus. Int J Mol Sci, 20:2506.
17.
CharernboonT, LerthattasilpT, SupasitthumrongT. 2021. Effectiveness of cannabinoids for treatment of dementia: a systematic review of randomized controlled trials. Clin Gerontol, 44:16–24.
18.
ChungH, ParkK, JangHJ, et al.2020. Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid beta oligomers in vivo. Brain Struct Funct, 225:935–954.
19.
CollinT, ChatM, LucasMG, et al.2005. Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling. J Neurosci, 25:96–107.
20.
Dávila-BouziguetE, Targa-FabraG, ÁvilaJ, SorianoE, PascualM. 2019. Differential accumulation of Tau phosphorylated at residues Thr231, Ser262 and Thr205 in hippocampal interneurons and its modulation by Tau mutations (VLW) and amyloid-β peptide. Neurobiol Dis, 125:232–244.
21.
DecressacM, PrestozL, VeranJ, et al.2009. Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice. Neurobiol Dis, 34:441–449.
22.
Duarte-NevesJ, Pereira de AlmeidaL, CavadasC. 2016. Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiol Dis, 95:210–224.
23.
EspinozaC, GuzmanSJ, ZhangX, et al.2018. Parvalbumin + interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus. Nat Commun, 9:4605.
24.
FewsterPH, Griffin-BrooksS, MacGregorJ, et al.1991. A topographical pathway by which histopathological lesions disseminate through the brain of patients with alzheimer's disease. Dement Geriatr Cogn, Disord2:121–132.
25.
GhosalK, PimplikarSW. 2011. Aging and excitotoxic stress exacerbate neural circuit reorganization in amyloid precursor protein intracellular domain transgenic mice. Neurobiol Aging, 32:e1–e9.
26.
GonzálezI, Arévalo-SerranoJ, PérezJL, GonzaloP, Gonzalo-RuizA. 2008. Effects of β-amyloid peptide on the density of M2 muscarinic acetylcholine receptor protein in the hippocampus of the rat: relationship with GABA-, calcium-binding protein and somatostatin-containing cells. Neuropathol Appl Neurobiol, 34:506–522.
27.
HattiangadyB, RaoMS, ShettyGA, et al.2005. Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol, 195:353–371.
28.
HijaziS, HeistekTS, ScheltensP, et al.2019. Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer's disease. Mol Psychiatry, 25:3380–3398.
29.
HoeflingC, ShehabiE, KuhnP-H, et al.2019. Cell type-specific human APP transgene expression by hippocampal interneurons in the Tg2576 mouse model of Alzheimer's disease. Front Neurosci, 13:137.
30.
HollnagelJ-O, ElzoheiryS, GorgasK, et al.2019. Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer's disease amyloidosis. PLoS One, 14:e0209228.
31.
HoyerD, BellGI, BerelowitzM, et al.1995. Classification and nomenclature of somatostatin receptors. Trends Pharmacol Sci, 16:86–88.
32.
HuhS, BaekS-J, LeeK-H, et al.2016. The reemergence of long-term potentiation in aged Alzheimer's disease mouse model. Sci Rep, 6:29152.
33.
JanefjordE, MåågJLV, HarveyBS, et al.2014. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell Mol Neurobiol, 34:31–42.
34.
KissE, GorgasK, SchlicksuppA, et al.2016. Biphasic alteration of the inhibitory synapse scaffold protein gephyrin in early and late stages of an Alzheimer disease model. Am J Pathol 186,2279–2291.
35.
LeeS-H, SolteszI. 2011. Requirement for CB1 but not GABAB receptors in the cholecystokinin mediated inhibition of GABA release from cholecystokinin expressing basket cells. J Physiol, 589:891–902.
36.
LeungL, Andrews-ZwillingY, YoonSY, et al.2012. Apolipoprotein E4 causes age- and sex-dependent impairments of Hilar GABAergic interneurons and learning and memory deficits in mice. PLoS One, 7:e53569.
37.
LevengaJ, KrishnamurthyP, RajamohamedsaitH, et al.2013. Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments. ACTA Neuropathol Commun, 1:34.
38.
LiH, LiuY, TianD, et al.2020. Overview of cannabidiol (CBD) and its analogues: structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer's disease. Eur J Med Chem, 192:112163.
39.
LorethD, OzmenL, RevelFG, et al.2012. Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy. Neurobiol Dis, 47:1–12.
40.
MaharI, AlbuquerqueMS, Mondragon-RodriguezS, et al.2017. Phenotypic alterations in hippocampal NPY- and PV-expressing interneurons in a presymptomatic transgenic mouse model of Alzheimer's disease. Front Aging Neurosci, 8:327.
41.
Mondragon-RodriguezS, Salas-GallardoA, González-PereyraP, et al.2018. Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model. J Biol Chem, 293:8462–8472.
42.
MoherD, LiberatiA, TetzlaffJ, AltmanDG. 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ, 339:b2535; DOI: 10.1136/bmj.b2535.
43.
Moreno-GonzalezI, Baglietto-VargasD, Sanchez-VaroR, et al.2009. Extracellular amyloid-beta and cytotoxic glial activation induce significant entorhinal neuron loss in young PS1(M146L)/APP(751SL) mice. J Alzheimers Dis, 18:755–776.
NajmR, RaoA, HuangY. 2020. Too much tau in interneurons impairs adult hippocampal neurogenesis in Alzheimer's disease. Cell Stem Cell, 26:297–299.
46.
NishimuraS, BilgüvarK, IshigameK, et al.2015. Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development. PLoS One, 10:e0124295.
47.
OgnjanovskiN, SchaefferS, WuJ, et al.2017. Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation. Nat Commun, 8:1–14.
48.
PalopJJ, ChinJ, RobersonED, et al.2007. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron, 55:697–711.
49.
ParkK, LeeJ, JangHJ, et al.2020. Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid beta oligomers. BMC Biol, 18:7.
50.
PattersonC. 2018. World Alzheimer Report 2018—The State of the Art of Dementia Research: New Frontiers. London, United Kingdom: Alzheimer's Disease. International.
PetracheAL, RajulawallaA, ShiA, et al.2019. Aberrant excitatory-inhibitory synaptic mechanisms in entorhinal cortex microcircuits during the pathogenesis of Alzheimer's disease. Cereb Cortex, 29:1834–1850.
53.
PopovicM, Caballero-BledaM, KadishI, et al.2008. Subfield and layer-specific depletion in calbindin-D28K, calretinin and parvalbumin immunoreactivity in the dentate gyrus of amyloid precursor protein/presenilin 1 transgenic mice. Neuroscience, 155:182–191.
54.
RamosB, Baglietto-VargasD, del RioJC, et al.2006. Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1 × APP transgenic model of Alzheimer's disease. Neurobiol Aging, 27:1658–1672.
55.
RiceHC, MarcassaG, ChrysidouI, et al.2020. Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model. Mol Neurodegener, 15:3.
56.
RogersJH. 1987. Calretinin: a gene for a novel calcium-binding protein expressed principally in neurons. J Cell Biol, 105:1343–1353.
57.
RozyckaA, Liguz-LecznarM. 2017. The space where aging acts: focus on the GABAergic synapse. Aging Cell, 16:634–643.
58.
RubioSE, Vega-FloresG, MartínezA, et al.2012. Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer's disease. FASEB J, 6:4458–4467.
59.
ScheyerAF, MelisM, TrezzaV, et al.2019. Consequences of perinatal cannabis exposure. Trends Neurosci, 42:871–884.
60.
SchmeltzerSN, HermanJP, SahR. 2016. Neuropeptide Y (NPY) and posttraumatic stress disorder (PTSD): a translational update. Exp Neurol, 284(Pt B):196–210.
61.
SchmidLC, MittagM, PollS, et al.2016. Dysfunction of somatostatin-positive interneurons associated with memory deficits in an Alzheimer's disease model. Neuron, 92:114–125.
62.
SchweitzerP, MadambaSG, SigginsGR. 1998. Somatostatin increases a voltage-insensitive K + conductance in rat CA1 hippocampal neurons. J Neurophysiol, 79:1230–1238.
63.
SekiguchiH, HabuchiC, IritaniS, et al.2009. Expression of neprilysin, somatostatin and the somatostatin sst5 receptor in the hippocampal formation of brains from Alzheimer's disease patients. Psychogeriatrics, 9:132–138.
64.
ShelefA, BarakY, BergerU, et al.2016. Safety and efficacy of medical cannabis oil for behavioral and psychological symptoms of dementia: an-open label, add-on, pilot study. J Alzheimers Dis, 51:15–19.
65.
ShiA, PetracheAL, et al.2020. Preserved calretinin interneurons in an app model of Alzheimer's disease disrupt hippocampal inhibition via upregulated P2Y1 purinoreceptors. Cereb Cortex, 30:1272–1290.
66.
SinghL, LewisAS, ShiJ, et al.1991. Evidence for an involvement of the brain cholecystokinin B receptor in anxiety. Proc Natl Acad Sci U S A, 88:1130–1133.
67.
SnyderJS. 2019. Recalibrating the relevance of adult neurogenesis. Trends Neurosci, 42:164–178.
68.
SolarskiM, WangH, WilleH, et al.2018. Somatostatin in Alzheimer's disease: a new role for an old player. Prion, 12:1–8.
69.
SolerH, Dorca-ArévaloJ, GonzálezM, et al.2017. The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy. Neurobiol Aging, 49:40–51.
70.
SongJ, SunJ, MossJ, et al.2013. Parvalbumin interneurons mediate neuronal circuitry–neurogenesis coupling in the adult hippocampus. Nat Neurosci, 16:1728–1730.
71.
SpencerB, PotkarR, MetcalfJ, et al.2016. Systemic central nervous system (CNS)-targeted delivery of neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. J Biol Chem, 291:1905–1920.
72.
SpiegelAM, KohMT, VogtNM, et al.2013. Hilar interneuron vulnerability distinguishes aged rats with memory impairment. J Comp Neurol, 521:3508–3523.
73.
StefanelliT, BertolliniC, LüscherC, et al.2016. Hippocampal somatostatin interneurons control the size of neuronal memory ensembles. Neuron, 89:1074–1085.
74.
SundlerF, MoghimzadehE, HåkansonR, et al.1983. Nerve fibers in the gut and pancreas of the rat displaying neuropeptide-Y immunoreactivity—intrinsic and extrinsic origin. Cell Tissue Res, 230:487–493.
75.
TakahashiH, BrasnjevicI, RuttenBPF, et al.2010. Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer's disease. Brain Struct Funct, 214:145–160.
76.
VerdaguerE, BroxS, PetrovD, et al.2015. Vulnerability of calbindin, calretinin and parvalbumin in a transgenic/knock-in APPswe/PS1dE9 mouse model of Alzheimer disease together with disruption of hippocampal neurogenesis. Exp Gerontol, 69:176–188.
77.
VerretL, MannEO, HangGB, et al.2012. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell, 149:708–721.
78.
Vico VarelaE, EtterG, WilliamsS. 2019. Excitatory-inhibitory imbalance in Alzheimer's disease and therapeutic significance. Neurobiol Dis, 127:605–615.
79.
VilletteV, Poindessous-JazatF, BellessortB, et al.2012. A new neuronal target for beta-amyloid peptide in the rat hippocampus. Neurobiol Aging, 33:e1–e14.
80.
WagnerL, BjörkqvistM, LundhSH, et al.2016. Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease: increased NPY levels and differential degradation of the NPY1-30 fragment. J Neurochem, 137:820–837.
81.
WallerR, MandeyaM, VineyE, et al.2020. Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex. Neuropathology, 40:336–346.
82.
WangB, WangZ, SunL, et al.2014. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci, 34:13314–13325.
83.
WickhamJ, LedriM, BengzonJ, et al.2019. Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients. Sci Rep, 9:1–11.
84.
YangX, YaoC, TianT, et al.2018. A novel mechanism of memory loss in Alzheimer's disease mice via the degeneration of entorhinal–CA1 synapses. Mol Psychiatry, 23:199–210.
85.
ZalloF, GardenalE, VerkhratskyA, et al.2018. Loss of calretinin and parvalbumin positive interneurones in the hippocampal CA1 of aged Alzheimer's disease mice. Neurosci Lett, 681:19–25.
86.
ZhangH, ZhangL, ZhouD, et al.2017. Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease. Neurobiol Dis, 106:171–180.
87.
ZhangL, WeiX, ZhangYH, et al.2013. CCK-8S increased the filopodia and spines density in cultured hippocampal neurons of APP/PS1 and wild-type mice. Neurosci Lett, 542:47–52.
88.
ZhengJ, LiH-L, TianN, et al.2020. Interneuron accumulation of phosphorylated tau impairs adult hippocampal neurogenesis by suppressing GABAergic transmission. Cell Stem Cell, 26:331.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
