Platelet Proteomic Analysis Revealed Differential Pattern of Cytoskeletal- and Immune-Related Proteins at Early Stages of Alzheimer’s Disease

The incidence of dementia is increasing at an alarming rate, and has become a major public health concern. Alzheimer disease (AD) is the most common form of dementia and is characterized by progressive cognitive impairment. In addition to classical neuropathological features such as amyloid plaques and neurofibrillary tangles (NFT), accumulation of activated immune cells has been documented in the AD brain, suggesting a contribution of neuroinflammation in the pathogenesis of AD. Besides cognitive deterioration, non-cognitive symptoms, such as agitation, aggression, depression and psychosis, are often observed in demented patients, including those with AD, and these neuropsychological symptoms place a heavy burden on caregivers. These symptoms often exhibit sudden onset and tend to fluctuate over time, and in many cases, they are triggered by an infection in peripheral organs, suggesting that inflammation plays an important role in the pathogenesis of these non-cognitive symptoms. However, there is no mechanistic explanation for the relationship between inflammation and neuropsychiatric symptoms. Observations from experimental mouse models indicate that alteration of brain blood vessels, especially blood-brain barrier (BBB) dysfunction, may contribute to the relationship. The current review summarizes the results from recent studies on the relationship between inflammation and AD, while focusing on cerebrovascular alterations, which might provide an insight into the pathogenesis of cognitive/non-cognitive symptoms in AD patients and suggest a basis for the development of new therapeutic treatments for these conditions. Show more

The main component of Alzheimer's disease (AD) amyloid deposits is amyloid beta-peptide (A beta), a fragment of the larger amyloid precursor protein (APP). The cellular source of A beta is not known, but a circulatory origin has been postulated. We studied human blood from healthy individuals and found that platelets account for almost 90% of the total anti-A beta immunoreactivity detected in whole blood. Using reverse-phase HPLC, we identified a platelet peptide which corresponds to A beta by three criteria: (a) it shares a retention time with the synthetic A beta 1-40 peptide in two consecutive HPLC tests; (b) it interacts with two anti-A beta antibodies in separate ELISAs; and, (c) its partial N-terminal amino acid sequence closely matches that of A beta. The detection of this peptide in platelets indicates that, aside from the well-known non-amyloidogenic (secretory) pathway, the processing of APP in platelets from healthy individuals also involves an amyloidogenic pathway. These findings are consistent with the view that platelets are one of the major sources of A beta in the circulation. Show more

Immune activation and inflammation play significant roles in the pathogenesis of Alzheimer's disease (AD). To test whether AD patients showed systemic manifestations of inflammation, blood from 41 patients with early stages of AD and 31 aged-match elderly controls were evaluated. Cellular markers for monocyte/macrophage (MO) activation and CD8 T lymphocyte were increased in early AD patients. Expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), was decreased; however, plasma MCP-1 levels were significantly increased and were related to the degree of MO activation in AD. These findings suggest that AD pathogenesis may be influenced by systemic immunologic dysfunction and provides potential immunologic targets for therapeutic intervention. Show more