Age-related changes in the density and morphology of plaques and neurofibrillary tangles in Down syndrome brain

Summary Fifteen cases of Down syndrome between age 25–59 years were examined neuropathologically. A variety of histological methods were used to identify plaques and neurofibrillary tangles (NFT). All cases had some plaques or NFT, but their density was generally not high before the age of 40 years. Plaques and NFT tended to appear at about the same time although in somewhat different cortical areas. Changes appeared first in the dentate gyrus, subiculum, entorhinal and association neocortex. The stages in the evolution of plaque morphology were quantitated in the dentate gyrus. The earliest change was the extracellular accumulation of fibrillar material with the histological characteristics of amyloid. In the second stage there was an exuberant neuritic reaction with swollen processes that contained little or no paired helical filaments (PHF). Stage 1 and 2 plaques were seen predominantly between ages 25–38 years, and were not obviously associated with blood vessels or glial cells. In the third stage of plaque formation neurites appeared to degenerate, contained more PHF, and surrounded a compact core of amyloid. Stage 3 plaques were never very numerous, and were seen only between ages 48–55 years. Stage 4 plaques consisted of a cloud of silver-positive debris. They appeared to be the final stage and were the predominant morphological type in the dentate gyrus after age 48 years. Amyloid angiopathy was present only after age 48, and was a prominent finding in only three cases.Supported in part by The Committee for the American Memorial Hospital, and by grants NS 23973, MH/NS 31862 and AGO 5134     

Immunohistochemical analysis of ubiquilin‐1 in the human hippocampus: Association with neurofibrillary tangle pathology

This post mortem immunohistochemical study examined the localization and distribution of ubiquilin‐1 (UBL), a shuttle protein which interacts with ubiquitin and the proteasome, in the hippocampus from Alzheimer's disease (AD) dementia cases, and age‐matched cases without dementia. In Braak stages 0–I–II cases, UBL immunoreactivity was detected in a dense fiber network in the neuropil, and in the cell cytoplasm and nucleoplasm of neurons in Cornu Ammonis (CA) fields and dentate gyrus granular neurons. In Braak stages III‐IV and V‐VI cases, UBL immunoreactivity was reduced in the neuropil and in the cytoplasm of the majority of CA1 neurons; some CA1 pyramidal neurons and the majority of CA2/3 pyramidal, CA4 multipolar, and dentate granular neurons had markedly increased UBL immunoreactivity in the nucleoplasm. Dual immunofluorescence analysis of UBL and antibody clone AT8 revealed co‐localization most frequently in CA1 pyramidal neurons in Braak stage III‐IV and V‐VI cases. Further processing using the pan‐amyloid marker X‐34 revealed prominent UBL/X‐34 dual labeling of extracellular NFT confined to the CA1/subiculum in Braak stage V‐VI cases. Our results demonstrate that in AD hippocampus, early NFT changes are associated with neuronal up‐regulation of UBL in nucleoplasm, or its translocation from the cytoplasm to the nucleus. The perseverance of UBL changes in CA2/3, CA4 and dentate gyrus, generally considered as more resistant to NFT pathology, but not in the CA1, may mark a compensatory, potentially protective response to increased tau phosphorylation in hippocampal neurons; the failure of such a response may contribute to neuronal degeneration in end‐stage AD.     

Identification and Immunolocalization of a New Class of Proteoglycan (Keratan Sulfate) to the Neuritic Plaques of Alzheimer's Disease

Previous studies have demonstrated three distinct classes of proteoglycans (PGs)/glycosaminoglycans (GAGs) localized to the characteristic lesions (i.e., neuritic plaques, cerebrovascular amyloid deposits, and neurofibrillary tangles) of Alzheimer's disease (AD). These include heparan sulfate (i.e., perlecan), dermatan sulfate (i.e., decorin), and chondroitin sulfate PGs/GAGs. In the present study, two different antibodies demonstrated the presence of a new class of PG (i.e., keratan sulfate) in the neuritic plaques of AD. A synaptic vesicle keratan sulfate PG (known as SV2PG) was detected by the monoclonal antibodies, anti-SV2 and anti-SV4, which recognize the keratan sulfate core protein and GAG chains, of the SV2PG antigen, respectively. Both antibodies immunolocalized SV2PG primarily to synapses and to dystrophic neurites within neuritic plaques of AD and normal aged brain. The SV2PG was not immunolocalized to diffuse plaques, cerebrovascular amyloid deposits, or neurofibrillary tangles in AD or normal aged brain. SV2PG immunoreactivity in AD brain was similar in distribution to synaptophysin and showed apparent reduced immunoreactivity in AD cortex in comparison to age-matched controls. In conjunction with previous studies, these results now suggest that within the neuritic plaques of AD, there are at least four different classes of PGs present. Although heparan sulfate PGs are still the only class of PG immunolocalized to amyloid fibrils within the neuritic plaques of AD, the specific immunolocalization of keratan sulfate, dermatan sulfate, and chondroitin sulfate containing PGs to the periphery of plaques, suggests that these particular PGs/GAGs may also play distinct and important roles in neuritic plaque pathogenesis.     

Variations in the neuropathology of familial Alzheimer’s disease

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant familial Alzheimer’s disease (AD). PSEN1 and PSEN2 are essential components of the γ-secretase complex, which cleaves APP to affect Aβ processing. Disruptions in Aβ processing have been hypothesised to be the major cause of AD (the amyloid cascade hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular, these cases have average greater hippocampal atrophy and NFT, more significant cortical Aβ42 plaque deposition and more substantial inflammation. Enhanced cerebral Aβ40 angiopathy is a feature of many cases, but particularly those with APP mutations where it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The mechanisms driving these pathological differences in AD are discussed.     

Neuropathologic correlates of activities of daily living in Alzheimer disease

Functional status, reflected by measures of activities of daily living (ADLs), deteriorates as Alzheimer disease (AD) progresses. Decline in activities of daily living may be mediated by executive and frontal lobe dysfunction. The objective of this study was to examine the relationship between activities of daily living and pathologic burden in Alzheimer disease. Twenty two subjects with definite Alzheimer disease were selected from the UCLA ADRC neuropathology database. A total activities of daily living score was derived from the Retrospective Collateral Dementia Interview-Revised (RCDI-R) questionnaire, which was administered to caregivers of autopsied subjects included in the study. Neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were performed for 8 brain regions. There was a significant positive correlation between total activities of daily living score (higher scores indicate more disability) and mean neuritic plaques and neurofibrillary tangle counts (r = 0.671, P = 0.001, and r = 0.542, P = 0.009, resp), as well as CA1 and prosubiculum neuritic plaques and neurofibrillary tangle counts, right and left orbital frontal neuritic plaques counts, and occipital neuritic plaques count. Total activities of daily living score did not correlate with age at death, age at symptom onset, dementia duration, gender, or education. Deteriorating activities of daily living in Alzheimer Disease subjects correlate with greater overall pathologic burden and possibly selectively with involvement of the medial temporal, occipital, and orbital frontal regions.     

Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer's disease brain

Amyloid plaques, a well‐known hallmark of Alzheimer's disease (AD), are formed by aggregated β‐amyloid (Aβ). The cellular prion protein (PrPc) accumulates concomitantly with Aβ in amyloid plaques. One type of amyloid plaque, classified as a neuritic plaque, is composed of an amyloid core and surrounding dystrophic neurites. PrPc immunoreactivity reminiscent of dystrophic neurites is observed in neuritic plaques. Proteinase K treatment prior to immunohistochemistry removes PrPc immunoreactivity from amyloid plaques, whereas Aβ immunoreactivity is enhanced by this treatment. In the present study, we used a chemical pretreatment by a sarkosyl solution (0.1% sarkosyl, 75 mM NaOH, 2% NaCl), instead of proteinase K treatment, to evaluate PrPc accumulation within amyloid plaques. Since PrPc within amyloid plaques is removed by this chemical pretreatment, we can recognize that the PrP species deposits within amyloid plaques were PrPc. We could observe that PrPc accumulation in dystrophic neurites occurred differently compared with Aβ or hyperphosphorylated tau aggregation in the AD brain. These results could support the hypothesis that PrPc accumulation in dystrophic neurites reflects a response to impairments in cellular degradation, endocytosis, or transport mechanisms associated with AD rather than a non‐specific cross‐reactivity between PrPc and aggregated Aβ or tau.     

Alz-50 immunoreactivity in the hypothalamus of the normal and Alzheimer human and the rat

Alz-50 is a monoclonal antibody recognizing a 68 kilodalton protein that is abundant in Alzheimer's disease (AD) but not detectable by immunoblotting methods in normal brains. When used for immunohistochemistry in AD cortex, Alz-50 recognizes large numbers of neurofibrillary tangles (NFT), neuritic plaques, and some neurons that show no evidence of neurofibrillary degeneration by conventional histopathological staining methods. Alz-50 immunoreactivity is described at the light and electron microscopic levels in the hypothalamus of brains obtained at autopsy from normal and AD subjects. Alz-50 immunoreactivity in the rat hypothalamus is also described. A well-defined population of Alz-50 immunoreactive hypothalamic neurons was identified in both the normal human and rat. At the light microscopic level in the normal human, immunoreactive neurons were most concentrated in the periventricular region, but were also scattered throughout the arcuate nucleus (ARC), lateral hypothalamic area, and tuberal region. Immunoreactive fibers were seen in the periventricular region, dorsal division of the ventromedial nucleus (VMNd), ARC, and external layer of the median eminence (ME). In the rat, reactive neurons were seen only in the periventricular region, and reactive fibers were seen in the periventricular zone, medial preoptic nuclear complex, suprachiasmatic nucleus, VMNd, ARC, and external layer of the ME. Ultrastructurally, all immunoreactivity in the normal human and rat hypothalamus was associated with intraneuronal vesicles. In the AD hypothalamus, Alz-50 identified numerous senile plaques and NFT in addition to the cells and fibers that were stained in the normal brains. Immunoreactive plaques and NFT were most numerous in regions previously reported to undergo neurofibrillary degeneration. At the ultrastructural level, the immunoreactivity in the AD hypothalamus was associated with filaments as well as vesicles. The significance of the selective staining of a specific population of vesicles by Alz-50 is unknown; however, the present results suggest that it is independent of AD pathology.     

An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease

Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5‐HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5‐HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5‐HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non‐AD controls (NC) stratified into three Braaks' stages (Braak 0–II, NC; Braak III/IV and V/VI, AD). In the Braak 0–II group, 5‐HT1A‐immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5‐HT1A‐ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5‐HT1A‐ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A‐ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5‐HT1A receptors are mainly preserved until the end‐stage of NFT progression in AD. Thus, the utility of PET imaging using a 5‐HT1A‐specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.     

Transformation of degenerating neurofibrils into amyloid substance in Alzheimer's disease: histochemical and immunohistochemical studies

Degenerating neurofibrils (DNF), which are composed of paired helical filaments (PHF) and amyloid fibrils (AF), are the 2 characteristic pathological fibrillar deposits in Alzheimer cortex. These fibrils were simultaneously studied by 2 techniques: The immunolabelling with a specific antiserum raised against PHF and elective thioflavine S staining of AF. In neuronal perikaryons, neurofibrillary tangles (NFT) consist of 3 populations: firstly, strongly immunolabelled tangles were weakly thioflavine-stained. Secondly, less dense tangles were weakly immunolabelled but strongly thioflavine-stained. Thirdly, ghost tangles which correspond to extracellular NFT were exclusively thioflavine-stained. Thus, it is likely that NFT are degraded to form extracellular AF. Around neuritic plaques and some vessels with amyloid angiopathy, immunolabelled neurites, thioflavine-stained neurites and transition figures were also observed. On the other hand, the central core of plaques and pathological vessel walls were strongly thioflavine-stained but were never immunoreactive. In conclusion, these observations favour catabolism of PHF bundles found in NFT and in degenerating neurites into an amyloid substance. This amyloid substance seems different from other amyloid deposits found in the central core of neuritic plaques and vessel walls.     

Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla)

The two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta protein (Aβ) plaques and neurofibrillary tangles (NFT). Aβ pathology is a common feature in the aged nonhuman primate brain, whereas NFT are found almost exclusively in humans. Few studies have examined AD‐related pathology in great apes, which are the closest phylogenetic relatives of humans. In the present study, we examined Aβ and tau‐like lesions in the neocortex and hippocampus of aged male and female western lowland gorillas using immunohistochemistry and histochemistry. Analysis revealed an age‐related increase in Aβ‐immunoreactive plaques and vasculature in the gorilla brain. Aβ plaques were more abundant in the neocortex and hippocampus of females, whereas Aβ‐positive blood vessels were more widespread in male gorillas. Plaques were also Aβ40‐, Aβ42‐, and Aβ oligomer‐immunoreactive, but only weakly thioflavine S‐ or 6‐CN‐PiB‐positive in both sexes, indicative of the less fibrillar (diffuse) nature of Aβ plaques in gorillas. Although phosphorylated neurofilament immunostaining revealed a few dystrophic neurites and neurons, choline acetyltransferase‐immunoreactive fibers were not dystrophic. Neurons stained for the tau marker Alz50 were found in the neocortex and hippocampus of gorillas at all ages. Occasional Alz50‐, MC1‐, and AT8‐immunoreactive astrocyte and oligodendrocyte coiled bodies and neuritic clusters were seen in the neocortex and hippocampus of the oldest gorillas. This study demonstrates the spontaneous presence of both Aβ plaques and tau‐like lesions in the neocortex and hippocampus in old male and female western lowland gorillas, placing this species at relevance in the context of AD research. J. Comp. Neurol. 521:4318–4338, 2013. © 2013 Wiley Periodicals, Inc.     

Hippocampal lesions in dominantly inherited Alzheimer's disease

We compared hippocampal lesions in three pedigrees of Familial Alzheimer's Disease (FAD). In these pedigrees, the disease is inherited as an autosomal dominant disorder and has been linked to DNA markers on chromosome 21. In eight cases of FAD (four from one pedigree and two each from two others) we quantified neurofibrillary tangles (NFT) and senile plaques (SP) in hippocampal subdivision CA1-4, subiculum, presubiculum, and dentate gyrus. We observed consistent patterns of the distribution of lesions: The highest density of NFT and SP was present in CA1-2; virtually no SP or NFT were present in presubiculum; SP diameter was consistently greatest in CA4. We found no overall differences among pedigrees in total densities of NFT and SP, but statistical analyses disclosed that an uncommon type of SP was disproportionately present in two pedigrees. This type of SP was usually restricted to CA4, had a marked amyloid core devoid of argyrophilic neurites. These studies also disclosed inter- and intrafamilial heterogeneity of lesion distribution (including congophilic angiopathy and cerebellar plaques) in these three pedigrees.     

Distribution of chromogranin B-like immunoreactivity in the human hippocampus and its changes in Alzheimer’s disease

Synapse loss is crucially involved in cognitive decline in Alzheimer’s disease (AD). This study was performed to investigate the distribution and density of chromogranin B-like immunoreactivity in the hippocampus of control compared to AD brain. Chromogranin B is a large precursor molecule found in large dense-core vesicles. For immunocytochemistry we used an antiserum raised against a synthetic peptide (PE-11) present in the chromogranin B molecule. Chromogranin B-like immunoreactivity was concentrated in the terminal field of mossy fibers, the inner molecular layer of the dentate gyrus and in layer II of the entorhinal cortex. In AD, chromogranin B was detected in neuritic plaques. The density of chromogranin B-like immunoreactivity was significantly reduced in the inner molecular layer of the dentate gyrus and in layers II, III and V of the entorhinal cortex in AD brains. The present study demonstrates that chromogranin B is a marker for human hippocampal pathways. It is particularly suitable for studying nerve fibers terminating at the inner molecular layer of the dentate gyrus. It is present in neuritic plaques, and its density is reduced in a layer-specific manner. Received: 14 February 2000 / Accepted: 6 March 2000     

Stereologic analysis of hippocampal Alzheimer's disease pathology in the oldest-old: evidence for sparing of the entorhinal cortex and CA1 field

Several neuropathologic analyses postulate that Alzheimer disease (AD) in the oldest-old is associated with substantial neurofibrillary tangle (NFT) formation in the CA fields of the hippocampus and neuronal loss confined to the entorhinal cortex. All of these studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathological hallmarks in a global multivariate analysis. We present here a stereologic analysis of AD-related pathology in 12 oldest-old individuals including a complete assessment of total NFT, neuron numbers and amyloid volume in entorhinal cortex, CA fields, and dentate gyrus. The progression of NFT numbers and amyloid volume across the different Clinical Dementia Rating (CDR) groups was significantly slower in these cases compared to previously reported younger cases. Although patients with mild and moderate dementia showed significantly lower mean neuron numbers compared to CDR 0-0.5 cases, there was a marked overlap in individual values among CDR groups. A modest proportion of the variability in CDR scores was explained by NFT numbers in the CA2 field (18.1%) and the dentate gyrus (17.3%). In contrast, neither Nissl-stained neuron numbers nor total amyloid volume in the areas studied significantly predicted cognitive status. These data indicate that the occurrence and progression of AD-related pathologic changes are not an unavoidable consequence of aging. They also suggest that dementia in extreme aging depends more on the damage of hippocampal subdivisions commonly less affected than on severe NFT formation and neuronal loss in the CA1 field and entorhinal cortex.     

C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease

C-reactive protein (CRP) is a plasma acute-phase protein, normally not found in the brain. Previous studies have demonstrated the presence of CRP in the senile plaques of Alzheimer's disease (AD). In this study, the presence of CRP-like immunoreactivity in AD neurofibrillary tangles (NFT) was demonstrated following pre-treatment of tissue sections with formic acid. CRP-like immunoreactivity was observed in both extracellular and intracellular NFT and was co-localized with the NFT marker PHF-1 and the amyloid P component (AP). The CRP-like immunoreactive NFT were less numerous and more limited in their distribution than PHF-1 or AP-immunoreactive NFT. The present results further support an involvement of inflammatory processes in the etiology of AD.     

Neuronal and nonneuronal quantitative BACE immunocytochemical expression in the entorhinohippocampal and frontal regions in Alzheimer's disease

In this study, we quantitatively investigated the expression of beta-site amyloid precursor protein cleaving enzyme (BACE) in the entorhinohippocampal and frontal cortex of Alzheimer's disease (AD) and old control subjects. The semiquantitative estimation indicated that the intensity of BACE overall immunoreactivity did not differ significantly between AD and controls, but that a significantly stronger staining was observed in the hippocampal regions CA3-4 compared to other regions in both AD patients and controls. The quantitative estimation confirmed that the number of BACE-positive neuronal profiles was not significantly decreased in AD. However, some degeneration of BACE-positive profiles was attested by the colocalization of neurons expressing BACE and exhibiting neurofibrillary tangles (NFT), as well as by a decrease in the surface area of BACE-positive profiles. In addition, BACE immunocytochemical expression was observed in and around senile plaques (SP), as well as in reactive astrocytes. BACE-immunoreactive astrocytes were localized in the vicinity or close to the plaques and their number was significantly increased in AD entorhinal cortex. The higher amount of beta-amyloid SP and NFT in AD was not correlated with an increase in BACE immunoreactivity. Taken together, these data accent that AD progression does not require an increased neuronal BACE protein level, but suggest an active role of BACE in immunoreactive astrocytes. Moreover, the strong expression in controls and regions less vulnerable to AD puts forward the probable existence of alternate BACE functions.     

Butyrylcholinesterase in the life cycle of amyloid plaques

Deposits of diffuse β-amyloid (Aβ) may exist in the brain for many years before leading to neuritic degeneration and dementia. The factors that contribute to the putative transformation of the Aβ amyloid from a relatively inert to a pathogenic state remain unknown and may involve interactions with additional plaque consituents. Matching brain sections from 2 demented and 4 nondemented subjects were processed for the demonstration of Aβ immunoreactivity, butyrylchlinesterase (BChE) enzyme activity, and thioflavine S binding. Additional sections were processed for the concurrent demonstration of two or three of these markers. A comparative analysis of multiple cytoarchitectonic areas processed with each of these markers indicated that Aβ plaque deposits are likely to undergo three stages of maturation, ie, a “diffuse” thioflavine S–negative stage, a thioflavine S–positive (ie, compact) but nonneuritic stage, and a compact neuritic stage. A multiregional analysis showed that BChE-positive plaques were not found in cytoarchitectonic areas or cortical layers that contained only the thioflavine S–negative, diffuse type of Aβ plaques. The BChE-positive plaques were found only in areas containing thioflavine S–positive compact plaques, both neuritic and nonneuritic. Within such areas, almost all ( > 98%) BChE-containing plaques bound thioflavine S, and almost all (93%) thioflavine S plaques contained BChE. These results suggest that BChE becomes associated with amyloid plaques at approximately the same time that the Aβ deposit assumes a compact β-pleated conformation. BChE may therefore participate in the transformation of Aβ from an initially benign form to an eventually malignant form associated with neuritic tissue degeneration and clinical dementia.     

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus

Lysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid‐β. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown. This study aimed to quantify lysosomal vesicles at amyloid plaques in the human hippocampus. Lysosome‐associated membrane protein 1 (LAMP1)‐positive vesicles accumulated in both diffuse (Aβ42‐positive/AT8‐negative) and neuritic (Aβ42‐positive/AT8‐positive) plaques in all regions were analysed. In contrast to mouse models of Alzheimer's disease, however, not all amyloid plaques accumulated LAMP1‐positive lysosomal vesicles. Even at neuritic plaques, LAMP1 immunoreactivity was more abundant than phospho‐tau (AT8). Further, lysosomal vesicles colocalised weakly with phospho‐tau such that accumulation of lysosomal vesicles and phospho‐tau appeared to be spatially distinct events that occurred within dystrophic neurites. This quantitative study shows that diffuse plaques, as well as neuritic plaques, contain LAMP1 immunoreactivity in the human hippocampus.     

Aberrant localization of MAP5 immunoreactivity in the hippocampal formation in alzheimer's disease

Immunocytochemistry was used to examine MAP5 immunoreactivity in the hippocampal formation obtained postmortem from five elderly, normal individuals, six individuals with Alzheimer's disease (AD), and two “transition” cases that did not have a history of dementia but did exhibit significant AD pathology. In all of the cases examined, axonal staining was restricted to the mossy fibers and their terminal field in CA3 stratum lucidum. In control cases, MAP5 immunoreactivity was observed in the neuronal cytoplasm and the proximal portion of the apical dendrites of pyramidal and granule cells. In both AD and transition cases, increased intensity of immunostaining was observed in CA3 pyramidal, subicular, and dentate gyrus granule cell neurons. Within individual neurons, immunoreactivity filled the neuronal perikarya, including the nuclear region, and the apical dendrite. Punctate staining was observed in neuritic plaques, but neurofibrillary tangles and neuropil threads were not immunostained. The increase and altered distribution of MAP5 immunoreactivity in both vulnerable and nonvulnerable neurons in AD may reflect an aberrant sprouting response. The increased expression of early cytoskeletal proteins may be tolerated in some regions such as CA3, but not in others including CA1 where the increased expression appear to precede aberrant phosphorylation, proteolysis, and incorporation of cytoskeletal proteins into AD pathology. Alternatively, the results could reflect sprouting in response to the neuronal loss and degeneration.