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

Abstract

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.

Spatial Memory Consolidation is Associated with Induction of Several Lysine-Acetyltransferase (Histone Acetyltransferase) Expression Levels and H2B/H4 Acetylation-Dependent Transcriptional Events in the Rat Hippocampus

“…The combination of these lesions impairs declarative-like memory functions in rats and model aspects of anterograde amnesia, as described in AD patients (Cassel et al, 2008). Thus, any method of physiologically modulating CBP levels is of prime interest for memory-related diseases.…”

“…This newly generated HAT activity is likely to further ensure specific acetylatedhistone-dependent events, in particular on H4 and H2B histones, which we found to be regulated on memory/ plasticity-related genes during the ongoing process of memory formation. In addition, regulations of CBP and histone acetylation were lost in a rat model of hippocampal denervation presenting two major degenerative features found in AD, namely neuronal loss in the basal forebrain (BF) and the entorhinal cortex (EC), and in which spatial memory consolidation does not occur (Cassel et al, 2008;Traissard et al, 2007). Our findings emphasize that spatial memory dysfunctions, as seen in AD, could be the result of altered genetic (CBP expression) and epigenetic (histone acetylation) regulations in the hippocampus, otherwise controlled by these neuronal inputs (ie, glutamatergic and cholinergic).…”

Astroglia in dementia and Alzheimer's disease

“…56 Hence, substantial efforts were invested in producing relevant animal models of AD (for a comprehensive review of literature, see references 57,58 ). Initial models of AD were simply normal aged animals, 59,60 which showed cholinergic involution associated (in monkeys) with b-amyloid deposition.…”

“…After identification of the pathogenic mutations of tau in FTDP-17, different transgenic models with clear neuronal NFT were produced. 57,58 The Tau P301L (single-transgenic mice expressing the Pro 301 to Leu tau mutation (P301L)) mutation is the most common associated mutation linked with FTDP-17. 78 Transgenic mice overexpressing Tau P301L exhibit neurofibrillary tangles without Ab pathology and/or neuronal loss, except for the spinal cord (Table 1; 58,78 ).…”

Lesions and Genes: On the Edge of Improved Isomorphic Models for Alzheimer’s Disease?

“…It is not to exclude that the progression of the disease could rely, at least partly, on some vicious cycle involving complex interactions between neuronal damage, tauopathy and amyloidopathy. As stated in the conclusion of their short review presented in this issue, Cassel et al [5] refer to 2 recent studies that have tackled such a question with some success, either with selective basal forebrain cholinergic lesions in CRND8 transgenic mice [6] or with selective noradrenergic lesions in the locus ceruleus of APP23 transgenic mice [7] . Therefore, new breakthroughs in the understanding of some aspects of AD, of its progression and of the dysfunctions accounting for its cognitive correlates may arise from the convergence of the respective advantages of nontransgenic and transgenic models and the possibility of performing more specific lesions, opening up exciting fields of research where one will be able to reconcile the cognitive dysfunctions and the molecular signals that are specific to AD.…”