Sequence of Aβ-Protein Deposition in the Human Medial Temporal Lobe

Abstract

The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

“…Subsequently, all cases were classified neuropathologically according to Braak-NFT staging system [4]. Aβ-protein deposition staging was performed according to the amyloid nomenclature proposed by Thal and collaborators [73]. The Vibratome blocks were cut at 50 µm and processed for immunostaining and histochemistry.…”

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease

“…Ab-deposits were detected by immunohistochemistry with an antibody raised against the Ab 17-24 -peptide (4G8, Signet) and by the use of the Campbell-Switzer silver technique. The evolutionary phases (0-4) of b-amyloid load in the medial temporal lobes of these subjects were determined as described by Thal et al 10,11 Staging for neurofibrillary changes (NFT-staging) was performed according to Braak and Braak. 12 Statistical analyses Genotype and allele frequencies between AD patients and control subjects were compared by Fisher's exact tests.…”

“…We assessed, by immunohistochemistry, the b-amyloid load in the medial temporal lobes of 58 elderly nondemented subjects by staging the expansion of Ab-deposition in the medial temporal lobe according to the phases described by Thal et al 10,11 The protective A/A genotype was specifically associated with low brain amyloid load (median for A/A: 0; median for non-A/ A: 2; P ¼ 0.030, Figure 1a) and had no impact on Braak's neurofibrillary tangle (NFT) staging 12 (P ¼ 0.280).…”

Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses

“…This hypothesis has been reinforced by evidence from transgenic (Tg) mouse models of AD in which overexpression of mutant APP results in amyloid deposition (3)(4)(5)(6)(7)(8)(9)(10). Neuritic dystrophy associated with the deposits of A␤ in AD brains is evidenced by progressive dendritic dystrophy within the hippocampal complex (11)(12)(13)(14)(15)(16)(17). Although the assumption has been that A␤ deposition leads to neuritic dystrophy that would impair hippocampal function (18,19), the causal links between the deposition and pathology have been largely inferential, with minimal data available on the time course of these events.…”