Alzheimer’s disease, brain immune privilege and memory: a hypothesis

Abstract

The most distinctive feature of Alzheimer's disease (AD) is the specific degeneration of the neurons involved in memory consolidation, storage, and retrieval. Patients suffering from AD forget basic information about their past, loose linguistic and calculative abilities and communication skills. Thus, understanding the etiology of AD may provide insights into the mechanisms of memory and vice versa. The brain is an immunologically privileged site protected from the organism's immune reactions by the blood-brain barrier (BBB). All risk factors for AD (both cardiovascular and genetic) lead to destruction of the BBB. Evidence emerging from recent literature indicates that AD may have an autoimmune nature associated with BBB impairments. This hypothesis suggests that the process of memory consolidation involves the synthesis of novel macromolecules recognized by the immune system as "non-self" antigens. The objective of this paper is to stimulate new approaches to studies of neural mechanisms underpinning memory consolidation and its breakdown during AD. If the hypothesis on the autoimmune nature of AD is correct, the identification of the putative antigenic macromolecules might be critical to understanding the etiology and prevention of AD, as well as for elucidating cellular mechanisms of learning and memory.

Cobalamin deficiency, hyperhomocysteinemia, and dementia

“…To illustrate, cerebral amyloid angiopathy occurs in many cases of DBT248 and in most cases of AD,46,260,261 where increased vessel atrophy,262 decreased microvascular density,262 reduced temporal lobe blood flow,263,264 and spontaneous cerebral emboli265,266 are other significant findings. Hcy permeates through the BBB,267,268 causing BBB dysfunction,74,76–78 which is observed in AD,247,269 DBT,220,223,256,270 and VaD,75 allowing easy influx for a wide variety of proteins to cerebral interstitial fluid271,272 and vice versa 273. With BBB dysfunction, brain parenchyma likely becomes less protected from toxic effects of systemic HHcy,229 which increases risk for acute macrovascular disease, or strokes,7,21,70,84,85,87,151,223,274–279 causing loss of volume, and chronic microvascular disease, or ischemia,135,220,280 causing loss of cortical-to-subcortical connections,248 occasionally with findings as those in DBT 220,223,281,282…”

Neuroimmunomodulatory steroids in Alzheimer dementia

“…From an immunological standpoint, the brain is a privileged organ and BBB protects it from an autoimmune attack. The possible mechanisms behind this were excellently reviewed by Arshavsky [70]. A brief survey of his thesis pointing out sites of possible steroid actions follows.…”

Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia

“…Under physiological conditions, synaptic connected proteins are not recognized by immune system cells. However, once cerebral ischemia-reperfusion injured BBB, the primary and new connected proteins are recognized by immune system cells, which lead to autoimmune response and subsequent secretion of inflammatory factors from activated immune cells (Arshavsky 2006;Sardi et al 2011). RT1-N1 referred to the class I major histocompatibility and was responsible for antigen processing and presentation, the key step of triggering autoimmune response.…”