Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease
Abstract
The perforant pathway originates from the entorhinal cortex of the anterior parahippocampal gyrus and terminates on the outer dendritic branches of the granule cells of the dentate gyrus and pyramidal cells of the subiculum and hippocampus. It carries the principal cortical input to the hippocampal formation. Destruction of the perforant pathway in experimental animals leads to a partial deafferentation of its target neurons, followed by a robust sprouting of acetylcholinesterase (AChE) terminals in the deafferented perforant pathway zone. In Alzheimer's disease, the cells of origin of the perforant pathway are laden with neurofibrillary tangles. AChE staining in the terminal zone of the perforant pathway in Alzheimer's disease shows several distinct patterns that are not found in control brains. These changes are consistent with the results of experimental studies demonstrating reinnervation in laboratory mammals, including nonhuman primates. The results suggest that in Alzheimer's disease sprouting of AChE-containing systems occurs in the hippocampal formation in response to disease-related cellular damage in the entorhinal cortex.
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The first neurons affected in Alzheimer disease are layer II entorhinal cortex neurons that give rise to the perforant pathway.
“The first neurons to be affected are in layer II of entorhinal cortex (EC), the neurons that give rise to the perforant pathway, the single major projection linking the cerebral cortex with the hippocampus (Gomez-Isla et al., 1996; Hyman et al., 1987).”
From Propagation of Tau Pathology in a Model of Early Alzheimer's Disease (2012) · cites this paper as Hyman et al., 1987
Cites
Alzheimer's Disease and Senile Dementia: Loss of Neurons in the Basal Forebrain
Whitehouse, P., Price, D., Struble, R., Clark, A., Coyle, J., & DeLong, M. R. (1982) · Science · doi:10.1126/science.7058341 · Cited by 3,627 · see citing works
SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE
DAVIES, P. (1976) · The Lancet · doi:10.1016/s0140-6736(76)91936-x · Cited by 3,565 · see citing works
Alzheimer's disease: cell-specific pathology isolates the hippocampal formation.
Hyman, B. T., Van Hoesen, G. W., Damasio, A. R., & Barnes, C. L. (1984) · Science · doi:10.1126/science.6474172 · Cited by 2,268 · see citing works
Self-citationSenile dementia of the Alzheimer type
Terry, R. D., & Katzman, R. (1983) · Annals of Neurology · doi:10.1002/ana.410140502 · Cited by 831 · see citing works
Arendt, T., Bigl, V., Arendt, A., & Tennstedt, A. (1983) · Acta Neuropathologica · doi:10.1007/bf00697388 · Cited by 817 · see citing works
Perforant pathway changes and the memory impairment of Alzheimer's disease
Hyman, B. T., Van Hoesen, G. W., Kromer, L. J., & Damasio, A. R. (1986) · Annals of Neurology · doi:10.1002/ana.410200406 · Cited by 672 · see citing works
Self-citationThe parahippocampal gyrus: New observations regarding its cortical connections in the monkey
Hoesen, G. W. V. (1982) · Trends in Neurosciences · doi:10.1016/0166-2236(82)90201-6 · Cited by 624 · see citing works
The Prevalence and Malignancy of Alzheimer Disease
Katzman, R. (1976) · Archives of Neurology · doi:10.1001/archneur.1976.00500040001001 · Cited by 623 · see citing works
Distribution of acetyl cholinesterase in the hippocampal region of the guinea pig
Geneser-Jensen, F. A., & Blackstad, T. W. (1971) · Cell and Tissue Research · doi:10.1007/bf00325634 · Cited by 618 · see citing works
Prevalence and Malignancy of Alzheimer Disease
Lijtmaer, H., Fuld, P. A., & Katzman, R. (1976) · Archives of Neurology · doi:10.1001/archneur.1976.00500040088017 · Cited by 517 · see citing works
Dendritic Growth in the Aged Human Brain and Failure of Growth in Senile Dementia
Buell, S. J., & Coleman, P. D. (1979) · Science · doi:10.1126/science.493989 · Cited by 475 · see citing works
Plasticity of Hippocampal Circuitry in Alzheimer's Disease
Geddes, J. W., Monaghan, D. T., Cotman, C. W., Lott, I. T., Kim, R. C., & Chui, H. C. (1985) · Science · doi:10.1126/science.4071042 · Cited by 461 · see citing works
Induced acetylcholinesterase-rich layer in rat dentate gyrus following entorhinal lesions
LYNCH, G. S., Matthews, D. A., Mosko, S. S., Parks, T. N., & Cotman, C. W. (1972) · Brain Research · doi:10.1016/0006-8993(72)90533-1 · Cited by 449 · see citing works
Transmitter deficits in Alzheimer's disease
Hardy, J., Adolfsson, R., Alafuzoff, I. I., Bucht, G., Marcusson, J. O., Nyberg, P., Perdahl, E., Wester, P. O., & Winblad, B. G. (1985) · Neurochemistry International · doi:10.1016/0197-0186(85)90050-6 · Cited by 329 · see citing works
Braak, H., & Braak, E. (1985) · Acta Neuropathologica · doi:10.1007/bf00690836 · Cited by 287 · see citing works
Cell Biology of Synaptic Plasticity
Cotman, C. W., & Nieto‐Sampedro, M. (1984) · Science · doi:10.1126/science.6382610 · Cited by 273 · see citing works
Somatostatin immunoreactivity in neuritic plaques of Alzheimer's patients
Morrison, J. H., Rogers, J., Scherr, S., Benoit, R., & Bloom, F. E. (1985) · Nature · doi:10.1038/314090a0 · Cited by 264 · see citing works
Cholinergic Innervation in Neuritic Plaques
Struble, R. G., Cork, L. C., Whitehouse, P. J., & Price, D. L. (1982) · Science · doi:10.1126/science.6803359 · Cited by 249 · see citing works
Physiologic and essential tremor
Elble, R. J. (1986) · Neurology · doi:10.1212/wnl.36.2.225 · Cited by 231 · see citing works
Neuritic plaques in senile dementia of Alzheimer type: a Golgi analysis in the hippocampal region
Probst, A., Basler, V., Bron, B., & ULRICH, J. (1983) · Brain Research · doi:10.1016/0006-8993(83)90490-0 · Cited by 194 · see citing works
Cotman, C. W., Matthews, D. A., Taylor, D. A., & LYNCH, G. S. (1973) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.70.12.3473 · Cited by 191 · see citing works
In Vitro Evidence for Two Distinct Hippocampal Growth Factors: Basis of Neuronal Plasticity?
Crutcher, K. A., & Collins, F. (1982) · Science · doi:10.1126/science.7089542 · Cited by 179 · see citing works
Dendritic sprouting in Alzheimer's presenile dementia
Scheibel, A. B., & Tomiyasu, U. (1978) · Experimental Neurology · doi:10.1016/0014-4886(78)90164-4 · Cited by 176 · see citing works
Henke, H., & Lang, W. (1983) · Brain Research · doi:10.1016/0006-8993(83)90880-6 · Cited by 176 · see citing works
Denervation releases a neuronal survival factor in adult rat hippocampus
Gage, F. H., Björklund, A., & Stenevi, U. (1984) · Nature · doi:10.1038/308637a0 · Cited by 152 · see citing works
Brain Function, Synapse Renewal, and Plasticity
Cotman, C. W., & Sampedro, M. N. (1982) · Annual Review of Psychology · doi:10.1146/annurev.ps.33.020182.002103 · Cited by 131 · see citing works
Storm‐Mathisen, J. (1974) · Brain Research · doi:10.1016/0006-8993(74)90683-0 · Cited by 129 · see citing works
The distribution of acetylcholinesterase in the hippocampal formation of the monkey
Bakst, I., & Amaral, D. G. (1984) · The Journal of Comparative Neurology · doi:10.1002/cne.902250304 · Cited by 111 · see citing works
Versieck, J., Hoste, J., Barbier, F., et al. (1976) · The Lancet · doi:10.1016/s0140-6736(76)93046-4 · Cited by 106 · see citing works
Perry, R. H., Blessed, G., Perry, E. K., et al. (1980) · Age and Ageing · doi:10.1093/ageing/9.1.9 · Cited by 103 · see citing works
Promoting Functional Plasticity in the Damaged Nervous System
Freed, W. J., de Medinaceli, L., & Wyatt, R. J. (1985) · Science · doi:10.1126/science.3975624 · Cited by 100 · see citing works
Stanfield, B. B., & Cowan, W. M. (1982) · Brain Research · doi:10.1016/0006-8993(82)90619-9 · Cited by 93 · see citing works
Somatostatin-like immunoreactivity within neuritic plaques
Armstrong, D. M., LeRoy, S., Shields, D., & Terry, R. D. (1985) · Brain Research · doi:10.1016/0006-8993(85)90249-5 · Cited by 88 · see citing works
Replacement of damaged cortical projections by homotypic transplants of entorhinal cortex
Gibbs, R. B., Harris, E. W., & Cotman, C. W. (1985) · The Journal of Comparative Neurology · doi:10.1002/cne.902370104 · Cited by 88 · see citing works
Neural Systems of the Non‐human Primate Forebrain Implicated in Memorya
Hoesen, G. W. V. (1985) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1985.tb37582.x · Cited by 64 · see citing works
Local regulation of compensatory noradrenergic hyperactivity in the partially denervated hippocampus
Gage, F. H., Björklund, A., & Stenevi, U. (1983) · Nature · doi:10.1038/303819a0 · Cited by 59 · see citing works
The histochemical architecture of the Ammon's horn as related to its selective vulnerability
Friede, R. L. (1966) · Acta Neuropathologica · doi:10.1007/bf00691077 · Cited by 43 · see citing works
Wilson, R. C., Levy, W. B., & Steward, O. (1979) · Brain Research · doi:10.1016/0006-8993(79)90870-9 · Cited by 42 · see citing works
Lesion-Induced Sprouting in the Rat Dentate Gyrus Is Inhibited by Repeated Ethanol Administration
West, J. R., Lind, M. D., Demuth, R. M., et al. (1982) · Science · doi:10.1126/science.218.4574.808 · Cited by 41 · see citing works
LOSS OF LARGE NEURONS OF THE MEDIAL SEPTAL NUCLEUS IN AN AUTOPSY CASE OF ALZHEIMERʼS DISEASE
Nakano, I., & Hirano, A. (1982) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-198205000-00010 · Cited by 41 · see citing works
Some enzyme histochemical characteristics of the human hippocampus
Mellgren, S. I., Harkmark, W., & Srebro, B. (1977) · Cell and Tissue Research · doi:10.1007/bf00221768 · Cited by 32 · see citing works
Screening for neurofibrillary tangles and argyrophilic plaques with Congo Red and polarized light.
Stokes, M., & Trickey, R. J. (1973) · Journal of Clinical Pathology · doi:10.1136/jcp.26.3.241 · Cited by 31 · see citing works
Chen, L.-L., Hoesen, G. W. V., Barnes, C. L., et al. (1983) · Brain Research · doi:10.1016/0006-8993(83)90583-8 · Cited by 20 · see citing works
Role of the senile plaque in neuropeptide deficits of Alzheimer's disease
Kulmala, H. K., & Hutton, J. T. (1985) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/0278-5846(85)90029-6 · Cited by 5 · see citing works
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Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397 · see citing works
Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606 · see citing works
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Minoshima, S., Giordani, B., Berent, S., Frey, K. A., Foster, N. L., & Kuhl, D. E. (1997) · Annals of Neurology · doi:10.1002/ana.410420114 · Cited by 1,802 · see citing works
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.033 · Cited by 1,427 · see citing works
Self-citationDeKosky, S. T., Ikonomovic, M. D., Styren, S. D., Beckett, L., Wisniewski, S., Bennett, D. A., Cochran, E. J., Kordower, J. H., & Mufson, E. J. (2002) · Annals of Neurology · doi:10.1002/ana.10069 · Cited by 686 · see citing works
Hasselmo, M., & Schnell, E. (1994) · The Journal of Neuroscience · doi:10.1523/jneurosci.14-06-03898.1994 · Cited by 466 · see citing works
Arendt, T., Brückner, M. K., Lange, M., & Bigl, V. (1992) · Neurochemistry International · doi:10.1016/0197-0186(92)90189-x · Cited by 314 · see citing works
Microangiopathy, the vascular basement membrane and Alzheimer's disease: a review
Perlmutter, L. S., & Chui, H. C. (1990) · Brain Research Bulletin · doi:10.1016/0361-9230(90)90007-m · Cited by 193 · see citing works
Stancu, I.-C., Vasconcelos, B., Ris, L., Wang, P., Villers, A., Peeraer, E., Buist, A., Terwel, D., Baatsen, P., Oyelami, T., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1413-4 · Cited by 143 · see citing works
Hyman, B. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-023749 · Cited by 39 · see citing works
Self-citation
- Authors
- Hyman, B. T., Kromer, L. J., & van Hoesen, G. W.
- Affiliations
- University of Iowa (US)
- ORCID
- Hyman, B. T.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 1987-03
- Volume
- 21
- Issue
- 3
- Pages
- 259-267
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2142746788
- Cited by
- 177
- References
- 44
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 4
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P0 NS 19632, NS-14944)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- perforant path, Alzheimer's disease, reinnervation, acetylcholinesterase, entorhinal cortex, deafferentation, neurofibrillary tangles, dentate gyrus, subiculum, hippocampal formation, cholinergic nerve terminals, sprouting
- MeSH terms
- Acetylcholinesterase, Aged, Aged, 80 and over, Alzheimer Disease, Hippocampus, Histocytochemistry, Humans, Limbic System, Neural Pathways, Neurofibrils, Neuronal Plasticity
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