Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Parkinson's disease: Mechanisms and models

Microglia: a sensor for pathological events in the CNS

Inflammation and Alzheimer's disease.

Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer9s disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down9s syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients9 brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

https://www.embopress.org/doi/pdf/10.15252/emmm.201606210

The amyloid hypothesis of Alzheimer's disease at 25 years

We detected large numbers of HLA-DR-positive reactive microglia (macrophages), along with Lewy bodies and free melanin, in the substantia nigra of all cases studied with Parkinson's disease (5) and parkinsonism with dementia (PD) (5). We found similar, but less extensive, pathology in the substantia nigra of six of nine cases of dementia of the Alzheimer type (DAT) but in only one of 11 age-matched nonneurologic cases. All dementia cases with a premortem diagnosis of DAT or PD showed large numbers of HLA-DR-positive reactive microglia and significant plaque and tangle counts in the hippocampus, as well as reduced cortical choline acetyltransferase activity. One of 11 nondemented controls showed mild evidence of similar cortical pathology. These data indicate that HLA-DR-positive reactive microglia are a sensitive index of neuropathologic activity. They suggest a frequent coexistence of DAT- and Parkinson-type pathology in elderly patients.

Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease.

Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR.

It has been hypothesized that idiopathic parkinsonism might be due to age-related attrition of dopamine neurons occurring long after an initial acute episode. We present evidence against this hypothesis, based on our finding of at least six times as many HLA-DR-positive microglia phagocytosing dopamine neurons in parkinsonian brains as in control brains. This difference indicates an active pathological process.

Rate of cell death in parkinsonism indicates active neuropathological process.

Involvement of the immune system in the pathogenesis of Alzheimer's disease was demonstrated in two ways: by the attachment of complement proteins to diseased tissue, and by the activation of cells associated with the immune system. Alzheimer brain tissue was stained immunohistochemically by antibodies to components of the classical, but not the alternative, complement pathway. Antibodies to C1q, C3d, and C4d stained senile plaques, dystrophic neurites, neuropil threads and some tangled neurons. Antibodies to a neoantigenic site on the C5b-9 membrane attack complex stained dystrophic neurites and many tangled neurons, but not senile plaques. Antibodies to Factor P and fraction Bb of Factor B, which are specific for the alternative complement pathway, did not stain Alzheimer brain tissue. The cellular immune response was evaluated by the presence of reactive microglia and by the infiltration of small numbers of T-cells into diseased brain tissue. Reactive microglia were identified by antibodies to HLA-DR, a class II major histocompatibility complex glycoprotein, and by enhanced staining with antibodies to leukocyte common antigen and the Fc gamma RI and Fc gamma RII receptors. T-cells were identified by antibodies to leukocyte common antigen, as well as the CD4 and CD8 surface proteins. Double immunostaining with antibodies to GFAP and MHC class I or class II antigens established that astrocytes, which are GFAP positive, do not express MHC antigens in Alzheimer's disease. Endothelial cells express MHC class I antigens while reactive microglia and some leukocytes express class II antigen.

S. Itagaki

Papers

Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease.

Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR.

Rate of cell death in parkinsonism indicates active neuropathological process.

Immune system response in Alzheimer's disease.