Cholinergic deafferentation of the rabbit cortex: a new animal model of Aβ deposition

Beach, Thomas G.; Potter, Pamela E.; Kuo, Yu Min; Emmerling, Mark R.; Durham, R.A.; Webster, Scott D.; Walker, Douglas G.; Sue, Lucia I.; Scott, Sarah; Layne, K. J.; Roher, Alex E.

doi:10.1016/s0304-3940(00)00916-2

Cited by 63 publications

(33 citation statements)

References 18 publications

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“…Indeed, there are some indications that lesions of the CBF or the entorhinal cortex influence APP and tau metabolism in their target regions as reported in rabbits and rats [e.g. 157,158 ]. Therefore, one might suggest that applying the double lesion to transgenic mice might amplify the amyloid and tangle pathologies.…”

Section: Transgenic and Lesion Models Are Complementary: Let's Combinmentioning

confidence: 99%

Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?

et al. 2008

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One century after Alzheimer’s initial report, a variety of animal models of Alzheimer’s disease (AD) are being used to mimic one or more pathological signs viewed as critical for the evolution of cognitive decline in dementia. Among the most common are, (a) traditional lesion models aimed at reproducing the degeneration of one of two key brain regions affected in AD, namely the cholinergic basal forebrain (CBF) and the transentorhinal region, and (b) transgenic mouse models aimed at reproducing AD histopathological hallmarks, namely amyloid plaques and neurofibrillary tangles. These models have provided valuable insights into the development and consequences of the pathology, but they have not consistently reproduced the severity of memory deficits exhibited in AD. The reasons for this lack of correspondence with the severity of expected deficits may include the limited replication of multiple neuropathology in potentially key brain regions. A recent lesion model in the rat found that severe memory impairment was obtained only when the two traditional lesions were combined together (i.e. conjoint CBF and entorhinal cortex lesions), indicative of a dramatic impact on cognitive function when there is coexisting, rather than isolated, damage in these two brain regions. It is proposed that combining AD transgenic mouse models with additional experimental damage to both the CBF and entorhinal regions might provide a unique opportunity to further understand the evolution of the disease and improve treatments of severe cognitive dysfunction in neurodegenerative dementias.

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Section: Transgenic and Lesion Models Are Complementary: Let's Combinmentioning

confidence: 99%

Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?

et al. 2008

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“…Although the 192IgG-SAP immunotoxin does not identify p75 LNTR in non-rodent species, an analogous antibody to the human p75 LNTR (clone ME20.4) has recently been found to identify the majority of ChAT-positive cells in Wxed tissue of the cat (Tremere et al, 2000). This antibody has also been conjugated to Saporin, and the ME20.4-SAP immunotoxin has been used to selectively lesion cholinergic cells in BF of primates (e.g., Fine et al, 1997), sheep (Ferreira et al, 2001) and rabbit (Beach et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex

2005

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“…The prevalence of AD increases exponentially with age, and the histopathology of AD affects virtually all humans who approach the maximum human life span [1,2] . The initial pathogenic event of AD therefore must lie within the physiologic process of aging.We have developed an animal model of AD that is initiated by cortical cholinergic deafferentation, a normal aging change in humans [3][4][5] . In the aging human cerebral cortex, cholinergic deafferentation begins around ages 40-50 [6, 7] and is shortly followed by biochemically detectable elevations of cortical A ␤ [8] and A ␤ deposition [9] .…”

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confidence: 99%

“…We have used an immunotoxin to induce cortical cholinergic deafferentation in the rabbit. The immunotoxin-treated rabbits develop up to 8-fold increases in cortical A ␤ 42 and A ␤ is deposited on cerebral blood vessels [4,5] . The dependence of lesion-induced A ␤ deposition on cholinergic processes has been demonstrated by its reduction with cholinergic therapy and by showing that lesioning of the noradrenergic locus ceruleus does not cause A ␤ deposition.…”

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confidence: 99%

Physiologic Origins of Age-Related β-Amyloid Deposition

Beach¹

2008

Neurodegener Dis

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Background: Brain β-amyloid (Aβ) deposition is an extremely common accompaniment of aging in humans and many other mammalian species. We hypothesized that normal physiological changes of aging cause Aβ deposition. Objective: Three normal physiological aging changes were induced in young adult rabbits to determine their effects on brain Aβ concentrations and deposition. The three changes were cortical cholinergic deafferentation, hypercholesterolemia and estrogen deprivation. Methods: Cortical cholinergic deafferentation was achieved through intracerebroventricular immunotoxin injection. Hypercholesterolemia was induced with a 2% cholesterol diet. Estrogen deprivation was modeled with ovariectomy. Results: Cortical cholinergic deafferentation resulted in an 8-fold increase in cortical Aβ₄₂ concentrations and cerebovascular Aβ deposition. Hypercholesterolemia increased cortical Aβ₄₂ 4.6-fold while ovariectomy increased cortical Aβ₄₂ 1.6-fold. Conclusion: At least three physiological changes of normal aging may underlie age-related brain Aβ accumulation and Alzheimer’s disease.

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Cholinergic deafferentation of the rabbit cortex: a new animal model of Aβ deposition

Cited by 63 publications

References 18 publications

Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?

Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?

Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex

Physiologic Origins of Age-Related β-Amyloid Deposition

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