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The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer's disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11-16 and 18-22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11-14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD.
Pubmed ID: 35292192 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 4, 2023.Consortium that developed brief, standardized and reliable procedures for the evaluation and diagnosis of patients with Alzheimer's disease (AD) and other dementias of the elderly. These procedures included data forms, flipbooks, guidebooks, brochures, instruction manuals and demonstration tapes, which are now available for purchase. The CERAD assessment material can be used for research purposes as well as for patient care. CERAD has developed several basic standardized instruments, each consisting of brief forms designed to gather data on normal persons as well as on cognitively impaired or behaviorally disturbed individuals. Such data permit the identification of dementia based on clinical, neuropsychological, behavioral or neuropathological criteria. Staff at participating CERAD sites were trained and certified to administer the assessment instruments and to evaluate the subjects enrolled in the study. Cases and controls were evaluated at entry and annually thereafter including (when possible) autopsy examination of the brain to track the natural progression of AD and to obtain neuropathological confirmation of the clinical diagnosis. The CERAD database has become a major resource for research in Alzheimer's disease. It contains longitudinal data for periods as long as seven years on the natural progression of the disorder as well as information on clinical and neuropsychological changes and neuropathological manifestations.
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