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The pathophysiology of Alzheimer’s disease has been looked into extensively during the past 20 years. Animal models have yielded main information to elucidate the pathogenetic mechanisms. It has become impossible to survey this rich literature in one paper.

This is why we will not discuss systematically the animal models the reader is referred to in another review by the same authors. Alzheimer’s disease pathology can be categorized into three general chapters lesions due to the deposition of positive lesions, those due to losses of negative lesions, and lastly, those due to the reactive mechanisms of inflammation and plasticity. The former ones are strong, easy to identify, and form the foundation of the diagnosis. The neuron and synapse losses are hard to assess they are not part of the diagnostic criteria but may be the changes more directly associated with the cognitive deficit.

Because macroscopic findings are a result of disease losses, they will be addressed after the microscopic information. Ab deposition is associated with a discrepancy between its production and removal. Ab peptide is removed from its precursor, the amyloid protein precursor or APP, a transmembrane protein, by two consecutive enzymatic activities cleaves APP in its extracellular domain and leaves behind a fragment named C99 which is secondarily cleaved by the transmembrane gamma-secretase complex containing presenilin.

The subcellular compartmentalization of these diseases successive cleavages is still debated. It is today, widely believed that the final steps occur in the endosomal lysosomal pathway. The deposits are a mixture of different Ab isoforms, some beginning at amino-acid 11 N-truncated isoforms or terminating at AA 39 to 42. A frequent form begins at position 3 with the first glutamine residue already cyclized to pyroglutamate.

The isoform which truncates at AA 42 includes two additional amino acids on the C-terminus of the peptide, i.e. includes a greater part inserted within the cell membrane; is more hydrophobic and liable to precipitate out from water solution. APP, presenilin 1, presenilin 2, diseases, mutations, alzheimer disease,  have been found to correlate with elevation in Ab production and the ratio of Ab42/Ab40. The Ab peptide spontaneously tends to oligomerize: oligomers or ADLL = Ab-derived diffusible ligands may be the toxic species. Oligomers likely are generated intracellularly.

The parenchymal deposits

The Ab peptide is typically not detectable by immunohistochemistry in the brains of healthy young adults disease. Ab disease deposition is found in some intellectually normal elderly, in patients with either restricted cognitive deficit mild cognitive impairment, MCI, or with full-blown sporadic or familial AD, and trisomy 21 patients. The terminology of Ab peptide deposition is ambiguous. The term senile plaque has been employed in so many varied contexts that it has lost its precision.

We tried voluntarily to restrict its use to the so-called mature, neuritic plaque particularly when applied to the lesion without specification on the technique that has been employed to make it visible. In other contexts and to clarify, all forms of extracellular accumulation are referred to as deposits, preceded by a qualifying term that indicates how they have been made visible e.g. Ab deposits are demonstrated by anti Ab antibodies, and amyloid deposits are demonstrated by Congo red or thioflavin S staining. A second descriptive word can specify their morphology: diffuse, focal, or stellate Ab deposits. The neuritic part of the plaque forms its corona.

The issue of intracellular Ab

The occurrence of Ab peptide disease in the neuronal cell body has been controversial extensively. There is now great controversy regarding the very existence and, if accepted, the significance of iAb. In a forthcoming paper, Irina Alafuzoff Leena et al., in the preparation team surveyed much of the literature on this subject. We are thankful to the authors to have allowed us to see their extensive analysis.

The inference that Ab accumulates in the cell body of the neuron is derived from immunohistochemical experiments. The labeling quality is dependent on numerous variables among which is the character of the pre-treatment used to recover the antigenicity. The application of heat pretreatment promotes the visualization of iAb, mesothelioma, ankylosing spondylitis, crohn’s disease, type 2 diabetes, lung cancer symptoms but formic acid hinders it. Formic acid is widely utilized to increase the IR of extracellular Ab.

The antibodies raised against the Ab peptide can then attack an epitope within the Ab sequence at least in the Ab peptide and full-length APP as well as all the fragments of APP with which the sequence of the epitope is encompassed. The antibodies disease elicited against the initial AA with gout treatment and heart failure symptoms the first NH2 may theoretically see both the Ab peptide and C-terminal fragment of APP following b-cleavage.

Topography of the deposits

The majority of the Ab deposits disease are in the gray matter while streaks of diffuse deposits can be observed in the white matter. At least two methods of staging this progression have been published in the Braak scheme, they only describe the progression as follows: at stage A, amyloid deposits are located in the basal segments of the cortex at stage B, all the isocortex is affected except for the primary cortices the hippocampus is lightly affected at stage C, deposits are visible in all parts of the isocortex including sensory and motor core fields.

There are five phases in parenchymal amyloid deposition for Thal et al.: briefly, the isocortex is engaged in phase 1, hippocampus and entorhinal cortex in phase 2, striatum and diencephalic nuclei in phase 3, brainstem nuclei in phase 4, and lastly the cerebellum and other brainstem nuclei pontine nuclei, locus coeruleus, parabrachial nuclei, reticular-tegmental nucleus, dorsal tegmental nucleus, and oral and central raphe nuclei in phase 5. Thal et al. have described, meanwhile, three steps in CAA, which do not align with Ab parenchyma’s five phases just described.

Conclusions

Our knowledge of AD pathology disease has advanced significantly in the past 20 years the lesion constituents have been characterized the clinical correlates of the modifications within patient cohorts or in the population at large have been examined extensively; the evolution of the pathology has been characterized.

New imaging methods and novel and highly effective animal models have contributed to the understanding of time course and the mechanisms of the lesions. But some fundamentals are still open the connection between Ab accumulation and tau pathology remains poorly understood the mechanism of sporadic AD is still controversial.

Enhanced Ab peptide production, impairment of its clearance, or primary disruption of tau metabolism are reasonable hypotheses that remain to be tested by new neuropathological observation, postmortem and in vivo.t The pathologies of Alzheimer’s disease involve protein accumulation, neuronal and synaptic losses disease, and changes associated with reactive processes. Extracellular Ab deposition is found in the parenchyma as diffuse, focal, or stellate deposits.
It can affect the vessel walls of arteries, veins, and capillaries.

The instances in which the vessel walls of capillaries are involved have a greater likelihood of possessing one or two page 4 alleles. Parenchymal and vascular Ab deposition occurs in a stepwise manner. Tau accumulation, arguably the most excellent histopathological correlate of the clinical symptoms, occurs in three forms: within the cell body of the neuron as a neurofibrillary tangle, within the dendrites neuropil threads, and within the axons constituting the senile plaque neuritis corona. The evolution of tau pathology is stepwise and stereotyped from the entorhinal cortex, via the hippocampus, to the neocortex. The neuronal loss is heterogeneous and specific.